Prostate cancer (PCa) is one of the most prevalent and malignant cancer types in men, which causes more than three-hundred thousand cancer death each year. At late stage of PCa progression, bone marrow is the most often metastatic site that constitutes almost 70% of metastatic cases of the PCa population. However, the characteristic for the osteo-philic property of PCa is still puzzling. Recent studies reported that the Wnt and Ras signaling pathways are pivotal in bone metastasis and that take parts in different cytological changes, but their crosstalk is not well studied. In this review, we focused on interactions between the Wnt and Ras signaling pathways during each stage of bone metastasis and present the fate of those interactions. This review contributes insights that can guide other researchers by unveiling more details with regard to bone metastasis and might also help in finding potential therapeutic regimens for preventing PCa bone metastasis. Bone marrow is the most frequent metastatic site of PCa, which include 72.8% of all metastatic cases, at over three times higher than the second most frequent site . Knowinge.g., colorectal cancer and mucinous ovarian cancer [Wnt signaling, either canonical or non-canonical, leads to PCa development, especially in castration-resistance PCa (CRPC) and metastasis . The Rasn cancer ,6,7. In The overall progression of PCa BM can be characterized into three main steps: cancer cell invasion and circulation, interaction with osteocytes, and homing toward bones . The fole.g., acute myeloid leukemia, hepatomas, and gliomas [During metastasis, PCa cells transform into mesenchymal-like cells, which helps cells to invade through the basal lamina and survive in the blood circulation without cell-cell interactions . The EMT gliomas ,13,14,15 gliomas . On the  gliomas . Moreove gliomas ,18. ThosNF-κB signaling pushes cancer metastasis in multiple directions, such as stimulating MMP expressions and regulating cell adhesion molecules, according to previous studies . The tumThe third signaling pathway that is involved in PCa BM is the phosphoinositide 3-kinase (PI3K)/Akt signaling cascade, which originates from the activation of the epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). In general, the activation of EGF and VEGF receptors (EGFR and VEGFR) stimulates the Ras/Raf/MAPK kinase (MEK)/MAPK signaling cascade, which is involved in tumor progression or the PI3K/Akt/mammalian target of rapamycin (mTOR) cascade that promotes cell growth and the EMT ,28. In Pet al., Ren et al., and Huang et al. showed that miR-145 is activated by p53 and it inhibits mesenchymal and cancer stem cell markers, like fibronectin, vimentin, cluster of differentiation 44 (CD44), and c-Myc via inhibiting two mediators: human enhancer of filamentation 1 (hEF1) and Krüppel-like factor 4 (KLF4) [Other minor mediators that are discovered to be associated with PCa BM include KDM8, miR-145, and CCCTC-binding factor (CTCF). In the previous paragraph, we discussed the inhibitory characteristics of the AR in PCa metastasis. However, KDM8, an AR transcriptional enhancer, which can accompany with AR binding to the enhancer and promoter region of ATPase family AAA domain-containing protein 2 (ANCCA) and enhancer of zeste homolog 2 (EZH2) gene, results in PCa metastasis, neuroendocrine differentiation, and growth promotion . Reports4 (KLF4) ,48,49. H4 (KLF4) . KLF4 is4 (KLF4) ,52,53. m4 (KLF4) . Siu et 4 (KLF4) . CTCF, a4 (KLF4) ,56,57. AWhy do circulating PCa cells migrate to bone? This question can be answered by the interactions among osteocytes, bone marrow stromal cells (BMSCs), and PCa cells. In the circulation, PCa cells need to against attack by immunocytes, especially natural killer (NK) cells . Accordivβ3/Smad5 cascade, CD44, and integrin avβ3/Src/rac1 signaling and activates CXCR7 and Akt, which upregulate NF-κB resulting in receptor activator of NF-κB ligand (RANKL) overexpression, which can induce osteoclastogenesis [PCa cells are attracted to chemokines that are released from osteocytes and BMSCs and migrate toward the bone marrow . In the ogenesis ,72,73,74ogenesis . Therefoogenesis . These iogenesis ,77. At togenesis ,79,80. T2+, hematopoietin, bone morphogenic proteins (BMPs), CXCL12, annexin A2 (ANXA2), and insulin-like growth factor (IGF) [As PCa cells land in bone marrow, a series of tissue changes occurs, including angiogenesis, the escape of PCa cells from dormancy, and niche formation . In nichor (IGF) ,84,85, aor (IGF) ,87. Locaor (IGF) . A revieor (IGF) . Furtheror (IGF) . Barkan or (IGF) . Finallyor (IGF) . The upror (IGF) . These hIn the above discussion, we collected and summarized recent knowledge of the mechanisms regulating PCa BM. In the following section, we discuss the impacts of the ras/MEK axis and Wnt/β-catenin signaling pathway in PCa BM and their crosstalk.AR) [Ras signaling is known to be involved in the proliferation and metastasis of various cancers, including breast cancer, colorectal cancer, and lung cancer . In breaAR) ,111, E-sAR) , miR-letAR) ,114,115,AR) , Ras andAR) ,118, EZHAR) ,120,121,AR) . In contAR)  and phosAR)  were ideThe Wnt signaling pathway is essential for prostate carcinogenesis, which is involved in the formation of the castration-resistant phenotype . Recent In PCa/osteocyte interactions, Wnt signaling plays a role in transmitting signals between PCa cells and osteocytes. Noggin is a signaling protein that is involved in bone and neuron development . PCa celet al., Wnt signaling helped circular PCa cells attach to osteoblasts via the secretion of WISP-1 in a paracrine manner. WISP-1 activates endothelin-1 (ET-1)/ET-1 receptor signaling, promotes MAPK signaling, and subsequently elevates α4β1 integrin expression, which is essential for PCa/osteoblast attachment [In the above sections, we summarized recent information on the roles of Wnt and Ras signaling in PCa metastasis. This information elucidates that Wnt signaling and Ras signaling might be responsible for different cytological activities, whereas they could synergistically accelerate PCa tumor progression . In facttachment .9, which inactivates its activity and results in β-catenin retention [In maintaining PCa stem cell homeostasis, mixed lineage kinase 3 (MLK-3), a MAPK member, promotes β-catenin’s interacts with KLF4 instead of TCF, and finally reduces EMT initiation ,151,152.etention . Those rDespite the diverse effects on PCa metastasis, Ras signaling and Wnt signaling are co-regulated by several upstream regulators. Rab25, a member of small GTPase that belongs to the Ras superfamily, is known as a direct activator of Ras signaling and Wnt signaling in various cancers, including hepatocellular carcinoma and non-small-cell lung cancer, but not yet in PCa ,155. In In this review, we elucidated the crosstalk between Wnt signaling and Ras signaling in BM of PCa cells, which is summarized in Moreover, the above studies all exhibited that the roles of Wnt and Ras signaling in PCa progression are not always concurrent. Sometimes they are antagonistic to each other. BM of PCa occurs through consecutive progression with different signaling modulators in which external growth factors are involved. What is the upstream modulator of Wnt and Ras in PCa progression? Recently, this question was partially answered. The dynamics of Wnt and Ras at each stage of PCa metastasis need to be clarified, and the details within each stage must be elucidated, in order to completely answer the question. Byne et al. have reviewed that castration-mediated osteoporosis might link to PCa BM which bone reformation might increase BM activity . Detail


VOC, JSC, fill factor, FF, and power conversion efficiency, PCE), fabrication method, device architecture, and operational stability are also summarized. Finally, a conclusion is drawn where a brief outlook highlights the challenges that hamper the future progress of Bi‐based optoelectronic devices and suggestions for future directions are provided.The remarkable optoelectronic properties and considerable performance of the organo lead‐halide perovskites (PVKs) in various optoelectronic applications grasp tremendous scientific attention. However, the existence of the toxic lead in these compounds is threatening human health and remains a major concern in the way of their commercialization. To address this issue, numerous nontoxic alternatives have been reported. Among these alternatives, bismuth‐based PVKs have emerged as a promising substitute because of similar optoelectronic properties and extended environmental stability. This work communicates briefly about the possible lead‐alternatives and explores bismuth‐based perovskites comprehensively, in terms of their structures, optoelectronic properties, and applications. A brief description of lead‐toxification is provided and the possible Pb‐alternatives from the periodic table are scrutinized. Then, the classification and crystal structures of various Bi‐based perovskites are elaborated on. Detailed optoelectronic properties of Bi‐based perovskites are also described and their optoelectronic applications are abridged. The overall photovoltaic applications along with device characteristics (i.e.,  The toxic‐lead in organometal‐halide perovskites is hindering their applications and readily needs a replacement. This work communicates briefly about the possible nontoxic lead alternatives and explores bismuth‐based perovskites comprehensively, in terms of their structures, optoelectronic properties, and applications. This work is helpful to improve the material and performance of the bismuth‐based perovskites to bring them on par with lead‐based perovskites. Still, perovskite solar‐cells (PSCs) hold the center of attention in the photovoltaic market by having the power conversion efficiency (PCE) that exceeds over 25%, making it a rival to the conventional silicon‐based solar‐cells.Owing to their enormous optical and electronic properties along with facile solution processability, organometal‐halide perovskite (PVKs) captivated the scientific community.1 PVK  Similarly, the vulnerability of PVKs to UV‐light could successfully be resolved by the down conversion, initiated by the metallic nanoparticles introduced into the device structure. Likewise, the issue of thermal decomposition could be dealt with the employment of 2D materials  on the top of the active PVK layer. Herein, our discussion will be limited to the toxicity of lead in organometal‐halide PVKs and their solution by lead‐free PVKs. For the detailed study of the decomposition in organometal‐halide PVKs, readers are directed to our previous review paper.Besides such peculiar advantages, many pitfalls are associated with PVK materials. For instance, they are extremely unstable against environmental factors, i.e., moisture ingress, thermal stress, and ultraviolet (UV) radiations. Moreover, organic–inorganic lead‐halide PVKs ride on the toxic bioaccumulative lead (Pb), which ultimately hinders its industrialization. Currently, the issue of moisture ingression is addressed partially by proper encapsulation of a device, surface passivation, and the combination of lower‐dimensional PVKs  with the bulk PVKs structures.4 Simi Unfortunately, Sn‐based PVKs were extremely unstable, i.e., oxidized rapidly from Sn2+ to Sn4+, thereby formed a completely different non‐PVK phase .To address the issue of toxicity, researchers are struggling to find environment‐friendly Pb‐free alternatives. In this regard, many materials have been introduced into the PVK‐structure; for instance, Sn‐based PVKs were introduced and were found to be more pronounced due to their excellent performance in solar‐cells with a considerable PCE of 12.04%.7 Unfo2+, Mg2+, Mn2+, Bi3+, Sb3+, etc. were also introduced. Herein, our discussion will be limited to the trivalent bismuth , which is expected to be the best replacement for Pb2+  due to the following advantages: i) outstanding environmental stability, ii) greater absorption coefficient (≈105 cm−1), iii. similar ionic radius to Pb2+, and iv) isoelectronicity with Pb (presence of 6s2electrons). Moreover, due to their octahedral‐coordinated structure , a longer carrier diffusion lifetime is expected from Bi‐based PVKs. These remarkable properties enabling Bi as a promising candidate to substitute the toxic Pb in the PVKs framework.Beside Sn, many other divalent and trivalent alternatives, e.g., Ge In the first section of this progress report, the toxicity of Pb and its lethal effects on the human body as well as the possible Pb‐alternatives including their advantages and drawbacks are discussed. The second portion is related to the structural details about the various classes  of the Bi‐based PVKs are provided. The third and fourth sections are devoted to the overall optoelectronic properties and applications of the Bi‐based PVKs, respectively. Finally, a brief outlook in terms of challenges remaining in the way of further development of the Bi‐based PVKs and our remarks to resolve these issues and step forward for its commercialization are given.After the pioneering work on Bi‐based PVK solar‐cells by Park et al., it has been widely utilized in the PVK structures and exercised extensively for many optoelectronic applications.16 In 2Ksp = 4.4 × 10−9 and even no safe threshold level of lead in blood is mentioned. Therefore, without proper encapsulation, rainwater can simply decompose the PVK‐structure and leaches the Pb down from the rooftop energy harvesting devices  that can easily contaminate the environment. Besides this, the toxic Pb used in such optoelectronic devices cannot be recycled as in the case of other energy harvesting devices. Lead particles when inhaled, are absorbed by the lungs and some of them are taken to the throat during mucociliary clearance where they are absorbed by the gastrointestinal system. Once the body has been disrupted by lead, there is no viable way to undo it. Lead ions, when diffused inside the blood can cause damage not only at the organ level but also at the cellular level, as summarized in Figure  In fact, the existence of lead in optoelectronic devices, which are exposed to the environment is an alarming threat to all living beings. Therefore, besides its tremendous advantages and excellent performance in the optoelectronic devices; for instance, higher PCE in PVKs solar‐cells, it readily needs a suitable substitute that is nontoxic at least lesser toxic than lead. This new urge triggered a novel research field based on lead‐free metal halide PVKs.Lead, as an essential element in the organometal halide PVKs has raised the concern of toxicity, which dwells to damage the ecosystem as the only level of lead exposure not detrimental to human health is zero. The solubility constant of lead in water, i.e., Figure  The elements imitating this electronic structure or at least following the order of the Pb electronic configuration are therefore preferred as potential alternatives. Consequently, elements with filled 6s‐orbitals  and almost empty p‐orbital (to fill up the conduction band) are inevitable to replace Pb in the PVKs framework. In this regard, numerous elements are in the list, which acquires the same or maybe better electronic properties than Pb. One way is to simply move up‐down or left‐right in or from the same group that belongs to Pb and figure out the best alternative in terms of similar electronic configuration. In Figure  Keeping in view the above considerations, the promising candidates for Pb substitution are summarized, as shown in Figure While replacing Pb, the electronic configuration of the typical lead‐halide PVKs should be taken into account where the valence band is made up of halide's p‐orbitals and lead's s‐orbitals, while conduction band is solely based on lead's p‐orbitals, as shown in Figure 20 The2.1 Therefore, both of these alternatives remained under the spotlight of the scientific community. Unfortunately, due to poor performance in the optoelectronic devices , Ge is less preferred as compared to Sn. Moreover, Ge‐based PVKs exhibited poor stability due to their oxidation from Ge2+ to Ge4+. The oxidation issue in Ge‐based PVKs was found to be even more severe than the Sn2+ because of the reduced inert electron pair, which also lead toward lower dimensionality and significantly reduced conductivities. Additionally, their smaller ionic radii, as well as distortion of its octahedron [GeX6]3−, eventually became the cause of a slightly high bandgap > 1.6 eV, which could have also contributed to its poor performance in PSCs. Owing to their lower enthalpies, Ge‐based PVKs also exhibited a greater defect formation, e.g., significantly high hole‐density. Therefore, regardless of their nontoxic nature, its defect chemistry and rapid oxidation restricted the PCE of Ge‐based solar‐cells below 5% and hindered their applications in photovoltaics.Tin (Sn) and Germanium (Ge) are the ultimate first‐class choice while looking for Pb‐free alternatives as they are more active and comparatively less toxic.22 The Despite enormous efforts, Sn‐based PVKs could gain only about 12% of PCE, which could not be retained for longer due to its unwanted oxidation from Sn2+ to Sn4+ in the air. Thus, resulted in poor reproducibility and eventually lead to the destruction of a device. Various strategies have been applied to overcome the issue of the oxidation state conversion; for instance, many additives have been added into the precursor solution of the Sn‐based PVKs, which unfortunately failed to stabilize the Sn in its bivalent form, see Figure Similarly, Sn‐based PVKs got more attention by having several distinguished properties; including direct bandgap, lower exciton binding energy, superior carrier mobility, etc.25 Des2.22+, Ca2+, Sr2+, and Ba2+) serve as another option to substitute the toxic Pb. Like, Sn‐ and Ge‐based PVKs, alkaline earth metals also form the same 3D PVKs structure, i.e., ABX3; where, A = , B = , and X = . They are nontoxic and exhibited better photoluminescence properties when doped with rare earth metals. Unfortunately, due to their higher bandgaps and environmental vulnerabilities, they also failed to deliver the desired device performance.Alkaline earth metals being earth‐abundant metals also share the same oxidation state as that of lead; therefore, candidates from this group  but no extraordinary progress regarding their device performance has been reported.Transition metals are found to be environmentally stable and their 2D‐layered structure made them favorable for more cation sites variations. In other words, they allowed a variety of organic cations due to their 2D body‐centered structure.29 Alt2.4 In this regard, La2NiMnO6 PVK compound was fabricated; however, its complicated fabrication process  made it extremely expensive and thus hindered its further reproducibility.Ferroelectric type materials were previously exploited for their magnetic properties but somehow it was also suggested that they could also be used as photoabsorbers.31 In 6]3‐ that eventually lead to a wider bandgap (>1.6), iii) unwanted oxidation, i.e., from Ge2+into Ge4+, and iv) poor solubility of their compounds in the organic solvents, resulting in an inappropriate morphology. These problems consequently deteriorated the device performance, e.g., yielded a lower PCE ≈0.2% with poor stability.From the above brief discussion, it can be recapitulated that up till now Sn and Ge are presumed to be relatively better options in terms of considerable PCE and less toxicity. However, Ge‐based PVKs analogs severely underperformed in PV devices; the reasons behind were, i) its smaller ionic radius, ii) distortion of their octahedron 3− complex where A‐cations fill‐up the voids at the terminal sides and block any further attachment. The general formula of 0D Bi‐based PVKs is A3Bi2X9 where MA3Bi2I9 (MBI) with hexagonal structure (space group P63/mmc) is extensively studied for various optoelectronic applications.A family of 0D Bi‐based PVKs exhibits a unique structure  amongst all the PVK crystals, which does not share its network in any direction; therefore, known as “0D.” To get a clear idea of the 0D Bi‐based PVKs structure, it is needed to understand the formation of bioctahedra in the structure. Basically, a single octahedron  are attached in such a way that it conforms into a 1D structure. Based on the octahedral connection, 1D Bi‐based PVKs can be subdivided into two categories: i) edge‐shared octahedra and ii) corner‐shared octahedra (zigzag symmetry), which are explained below.In such Bi‐based PVKs configurations, bismuth halide octahedra (BiXymmetry),12b wh3.2.13), where Bi is residing at the center of three halogen atoms, as marked in Figure 4]− chains are formed when one octahedron  shares its opposite edges  in such a way that four halogen atoms are bridged together , as shown in the Figure  Herein, a compound LiBiI4⋅5H2O is taken as an example of the edge‐shared 1D structure having space group C2/c and monoclinic crystal structure, as shown in Figure To understand the edge‐shared octahedral 1D configuration of Bi‐based PVK, it is necessary to focus on the edge of octahedron that is actually a Bi‐trihalide  form a 1D network by means of corner‐sharing , hence conforms into a zigzag chain, as shown in Figure  Therefore, the A‐site cations dictate how the chain should be formed and gives a 1D character to it. The BiX6 octahedra build up a zigzag symmetry by means of three different bonding pairs: i) bridging, ii) terminal trans to bridging, and iii) terminal cis to bridging. Ideally, bond lengths should be equal but here the case is different, as the bond lengths are such that bridging > cis > trans bridging bond. The bridging bond, i.e., Bi− I1 is the longest amongst the bonds and acts as a backbone of the inorganic chain, while Bi− I1, Bi− I2, and Bi− I3, Bi− I4 are cis and trans, respectively to the long bridging bonds, as shown in Figure 2AETH)BiI5 PVK with an orthorhombic crystal system, as indicated in Figure In such configuration, the distorted octahedra  Bi‐based PVK structure converts into a 2D corrugated layered defect PVK structure in two ways: a) replacing A‐site cation  with reduced size and b) replacing halogen atoms. Consider the same 0D Bi‐based PVK structure (discussed above) where AX3 layers formed a hexagonal closed pack structure  (h)6, ii) (hcc)2, and iii) (c)3, where one can find the separation of double octahedra Bi2X9 caused by (h)6 stacking mode. Bonding of a single halogen atom with octahedra is possible due to (c)3 stacking mode whereas (hcc)2 stacking mode allows both of the above networking.A typical 0D  while the other three atoms are farther from Bi, Figure 3) set inside AX3 layers in such a way that all bridging atoms are shared with three other octahedra, forming corrugated Bi2X9 layers, as shown in Figure  as shown in Figure 3Bi2I9 PVK compound with monoclinic structure (space group Pc) is taken as an example of a 2D corrugated structure, see Figure 2D Bi‐based PVKs crystal structure is closed to cubic (c)possible.41 Mor3.42B′B″X6, where A = cation, B′ = monovalent cation, B″ = trivalent cation, and X = halogens. To achieve such a 3D‐PVK structure, a heterovalent substitution of Pb2+ is required. This can be done by replacing a B‐site cation into two different elements such that one half of B‐site cation acquire a charge of 3+ and the other half acquire 1+ charge to preserve charge neutrality. Due to the replacement of a single metal cation in the B‐site, the overall crystal lattice expands twice as compared to the conventional 3D ABX3 PVK structure. Therefore, the structure is named as “double perovskite.” Moreover, in the case of conventional 3D ABX3 PVKs, a B‐site cation shares 6‐fold coordination, while in the case of double PVKs, a similar 3D structure is composed of alternative corner‐shared octahedra of B′X6 and B″X6 with cuboctahedral voids filled by A‐cations, as depicted in Figure 2AgBiBr6 (space group Fm3m) as an example of elpasolite, see Figure 3 PVK Figure 3D Bi‐based PVKs are also known as double perovskites or elpasolites, having a general formula Aovskite.”52 Mor4Better optoelectronic properties are prerequisites for optoelectronic devices, which make them the ultimate choice for better performance. These properties include photoabsorption, energy bandgap and its nature, photoemission, charge carrier mobilities, photoresponsivity, defect concentration, exciton binding energy, charge carrier lifetime, etc. In the following section, the important optoelectronic properties have been discussed with reference to bismuth.4.1Figure 3PVKs have energy bandgap near to this limit but as far as Bi‐based PVKs are concerned, they have relatively larger energy bandgaps. Nevertheless, the preliminary study reveals that MBI and Cs3Bi2I9 (CBI) exhibit comparable optical absorption to the conventional Pb‐based PVKs.On average, the earth receives about 71% of the total solar spectrum where the rest of 29% reflects back to the atmosphere. For harnessing solar energy efficiently, a single junction device is needed to have a bandgap (≈1.2‐1.3 eV) to fulfill the Shockley–Queisser limit,54Fig3 type PVKs. In Bi‐based PVKs, [BiX6 ]‐octahedral units constitute valence and conduction electronic states; therefore, structural dimensionality has a strong impact on optoelectronic properties. A detailed explanation of the optoelectronic properties of the overall Bi‐based PVKs is beyond the scope of this report. Herein, our discussion will be limited to the most frequently studied Bi‐based 0D PVK, i.e., A3Bi2X9 with A = Cs, FA, and MA. However, the optoelectronic properties of some other important Bi‐based PVKs will also be summarized.The classification of Bi‐based PVKs  distinguishes them from conventional ABXoperties.56 A d4.1.1 Unlike the Pb‐based conventional 3D‐PVKs (where the excitonic peak is predominated by the absorption band‐edge and the true bandgap could precisely be estimated); the case is twisted for lower dimensional Bi‐based PVKs, i.e., a strong excitonic peak is tempered with the band edge, masking the true bandgap. Therefore, a discrepancy is always found in the reported bandgaps of the Bi‐based PVKs. For example, the reported bandgaps for CBI are ranged from 1.9 to 2.8 eV. Similarly, the energy bandgap of the MBI is within the range of 1.75–2.94 eV. The bandgaps of the overall Bi‐based PVKs reported to date for solar‐cell applications are summarized in Figure Figure Bi‐based PVKs share the same electronic configuration as that of lead‐based PVKs, i.e., their conduction band electronic states comprise of partially filled Bi‐p orbitals and fully occupied valence band with Bi‐s and halides‐p orbitals. The energy bandgap is established between conduction band minimum and valence band maximum, as displayed in Figure 57 Unl see Figure The occurrence of the excitonic peak for 0D PVK  nanocrystals was reported at 2.56 eV where the bandgap (determined from the absorption onset) was observed at 2.86 eV,57 see It was suggested that the possible reasons for this variation in the bandgaps could be; i) crystal orientation, ii) crystallinity of material, and iii) defects concentration in the material. Usually, a single crystal has lesser defect sites with higher crystallinity, which results in a smaller bandgap. This is further justified when the single crystal is ground and observed, the deep red color is changed to an orange blue color, which indicates a blue shift in the wavelength. Moreover, this effect became even more pronounced in the case of thin films, where the defect sites and orientation are affected more.Furthermore, it has been reported that single crystal and thin films of the same Bi‐based PVK compound exhibited different optical bandgaps. For instance, dissimilar bandgaps for the single crystal (1.96 eV), polycrystalline powder (2.0 eV), and thin films (2.26 eV) were determined.59 It 4.1.2 As far as the energy bandgap of the 0D Bi‐based PVKs is concerned, MBI possesses a direct bandgap while both direct (at higher energy) and indirect (at lower energy) bandgaps are reported for the CBI. However, in some cases, an indirect bandgap for MBI is also reported, see Figure  It is noteworthy that in contrast to the 0D Bi‐based PVKs , the 2D Bi‐based PVKs (Rb3Bi2I9) nanocrystals (NCs) exhibited two prominent sharp absorption peaks at 2.28 eV (546 nm) and 2.65 eV (468 nm), respectively. Similar absorption characteristics have also been reported in bulk Rb3Bi2I9 and other 2D perovskites like Cs3Bi2Br9 (CBBr) and hybrid Ruddlesden–Popper perovskite. But neither Rb3Bi2I9 nor NCs have shown any measurable PL, which might have specified the presence of native defect states or nonradiative recombination in the bandgap region.Besides the width of the optical bandgap of a photoabsorber, the nature of the bandgap is also important. In the case of direct bandgap material, most of the absorbed light is converted into radiative transitions. Conversely, in the case of the indirect bandgap material, majority of the absorbed radiations are emitted as nonradiative transitions ; hence, most of the energy is lost.60 As 4.1.35 cm−1. Bi‐based PVKs performed well in both visible and infrared regions. The absorption between X‐5p valence states and Bi‐6p absorption states are responsible for these excellent absorption properties of Bi‐based PVKs. Moreover, its better absorption can also be attributed to the optical transition from Bi‐6s states  to Bi‐6p conduction states.The optical absorption coefficient of a material is crucial to exploit it for optoelectronic applications. In this regard, Bi‐based PVKs showed ideal photoabsorption characteristics with an optical absorption coefficient as high as 105 cm−1.55 Bi‐4.2 In the case of defect‐free material, photoluminescence (PL) peaks and absorption band edge are expected to occur at the same energy but for materials having defects, PL peak may deviate from the absorption band edge, known as Stoke's shift, which could be intrinsic or extrinsic in nature. Moreover, defects in the structure cause a broadening of the PL peak, which is common in Bi‐based PVKs. BiX6 octahedra in Bi‐based PVKs are prone to structural deformation as they need to maintain charge neutrality. Such structural deformation generates polarons, which are analogous to free electrons and create optically active states between valence and conduction bands, known as “self‐trapping states”; hence forms emission centers. In this way, excited electrons experience nonradiative transitions before reaching the respective energy levels. The occurrence of these self‐trapping states produces an emission with lower energies, which is the reason for red‐shifted wavelength corresponding to a large Stoke's shift and is intrinsic in nature. The occurrence of these trapping states is also observed theoretically by Mosconi et al.It is a spontaneous emission of light from a material , which helps to provide a direct analysis of the optical properties of surfaces and interfaces.67 In 3Bi2X9 single crystals has been experimentally measured at room temperature as well as at lower temperatures, as shown in Figure 3Bi2I9 did not show any PL response at room temperature. The broadening in the PL spectrum of the CBI was attributed to the local lattice distortion or octahedral distortion. Additionally, it was also observed that the PL properties of CBBr were sensitive to the phase transition, caused by a decrease in temperature; therefore, the mechanism of PL of CBBr was studied in the temperature range of 160–240 K. A red‐shift from 453 to 457 nm along with a decrease in PL intensity was observed and attributed to the nonradiative recombination initiated by the temperature above 200 K. In addition to single crystals, the PL properties of thin films and quantum dots (QDs) were also studied. For instance, all inorganic Cs3Bi2X9  QDs have demonstrated even a high PL quantum yield than the Pb‐based inorganic analogs. Along with excellent PL properties, such QDs exhibited extraordinary moisture and photostability, which were attributed to the negation of the defects caused by the smaller size effect.Furthermore, the PL of Aeratures,64 as  see Figure Other than the typical single broad PL peak, two separated PL emission peaks (at 2.66 and 2.28 eV) with narrow full‐width‐at‐half‐maxima were also reported for CBI NCs,57 see4.3Despite the existence of defects, the capability of semiconductor to maintain its optoelectronic properties is termed as defect tolerance nature of the material. Defects are inevitable during material processing . Optoelectronic properties are not severely affected by the defects formed exterior to the bandgap. Conversely, intraband deep level defects have decisive effects on the optoelectronic properties of a material. These defects subsequently pave a way for the nonradiative recombination or become trap centers by itself, hence restricting the charge transport.762 lone pairs, which tend to create antibonding interactions. To understand this, consider the electronic band structure of Bi‐halide, where Bi‐6p orbital hybridizes with halogen X‐5p orbitals, forming deeper states of the valence band as well the bottom part of the conduction band (conduction band minima). Similarly, Bi‐6s and X‐5p overlap to form the valence band minima (bonding) and valence band maxima (antibonding). Only one X‐5p orbital interacts with Bi‐6s and Bi‐6p orbitals, which form the middle of the valence band. Consequently, these interactions create the energy bandgap between valence band maxima (VBM) and conduction band minima (CBM), as presented in Figure Antibonding interaction at valence band maximum causes the defects to confine to shallow states at the band edges. Bi‐based PVKs are presumed to have defect tolerance capability due to active nsractions.77 To 3 while the nature of the CBM is different from Pb analog. It was also observed theoretically that MBI was expected to have a better defect tolerance nature in comparison to CBI. Likewise, it was reported previously for Bi‐based double PVKs (Cs2AgBiBr6) that due to the weak coupling of Bi‐6s and Br‐6p, it contributes less to the VBM. As a result, Ag acted as a shallow acceptor vacancy and could form p‐type conduction; hence, did not show better defect tolerance. Furthermore, it was suggested that the synthesis of Bi‐based double PVKs need to fulfill Br‐poor or Bi‐rich growth conditions to make these materials defects tolerant.Additionally, it has been reported that the nature of VBM formation of CBI is the same as in MAPbIb analog.80 It 4.4 A short laser pulse induces excitation in the material, as a result, exciton (electron–hole pair) is created that upon Coulombic‐interaction wants to recombine with each other. Time‐resolved PL measures the time of the excited electron until it recombines, known as carrier lifetime. For longer, the charge carriers (electron–hole pair) are separated, longer carrier lifetime is expected. Longer carrier lifetime suggests that charge extraction and transport becomes more efficient, which makes the material more favorable for the photovoltaic applications.Longer carrier lifetime is essential for better charge extraction that consequently leads toward better photovoltaic performance.82 A s However, the case of Cs2AgBiBr6 and Cs2AgBiCl6 was found to be an exception, i.e., they exhibited a faster exponential decay followed by a slower decay tail. Therefore, to fit those time‐resolved PL (TRPL) curves, bi‐ or even triexponential functions were used. The initial faster decay was attributed to the recombination centers or crystallographic defects, whereas the longest decay tail was accredited to the fundamental exciton lifetime, see Figure  The possible reason for this longer carrier lifetime could be the indirect bandgap and defect tolerance nature of the material. Moreover, it was reported that the decay lifetime was significantly different for single‐crystal (145 ns) and powder (54 ns) of Cs2AgBiBr6, which suggested that a powder sample has more defect sites. However, longer PL decay lifetime reported , which were not significantly different for the two samples and attributed to the fundamental recombination lifetime, as shown in Figure Reported lifetime for Pb‐free substitutes ranged between <0.1 ns to ≈10 ns.84 How4.5 For example, Machulin et al. reported a higher exciton binding energy of 279 meV for CBI 0D‐PVK. It was suggested that such a higher exciton binding energy could be the reason behind the ambiguity of the bandgap and crystal color. Similar higher exciton binding energy was reported in the ionic alkali halide compounds, which caused a larger Stoke's shift in absorption and emission spectra. Such high binding energy was responsible for the excitonic absorption peaks even at room temperature. Similarly, even higher exciton binding energy of 300 meV was reported for the MBI 0D‐PVK.Exciton binding energy is another essential parameter that governs the optoelectronic properties of the devices. Excitons having smaller binding energy can be separated easily, which prolongs their lifetime and carrier diffusion length. Due to their lower dimensionality and structure isolation, OD‐PVK structure  resulted in a higher exciton binding energy, exceeding a few 100s meV. However, they have the potential to exhibit optical properties comparable to the Pb‐based 3D metal halide PVKs.64 For4.6 Herein, our discussion will be limited to the space‐charge‐limited‐current (SCLC) method, which is frequently used for the calculation of the charge carrier mobility of the Bi‐based PVKs. In SCLS, current–voltage (IV) characteristics follow Lampert's theory of current in solids, which is divided into three regions, as indicated in Figure  i) At a lower voltage, the region (known as linear or Ohmic region), follows I ∝ V. ii) At higher biasing conductions carried out by traps, follows I ∝ nV> 3, known as trap‐filled limit (TFL) region. This region is helpful to estimate the trap concentration in the material. iii) The next is a Child regime, which is followed by Mott Gurney relation, i.e., I ∝ nV= 2, where mobility can be estimated by the Equation , ε is the dielectric constant of the material, ε0 is the permittivity of free space, and V is the applied voltage. Using SCLS calculation, the mobility of MBI was reported to be 29.7 cm2 V−1 s−1, which was comparable to the lead analogs, showed its applicability for the photovoltaics, see Figure  To ensure better carrier mobility, the quality of the thin film is essential, because a rough film (having pinholes) could lower the carrier mobility. For example, significantly lower carrier mobility, i.e., 3.47 × 10−7 cm2 V−1 s−1 was reported for the similar MBI PVK thin film, which was attributed to the inferior quality of the film, see Figure Charge carrier's mobility is drift velocity per unit electric field, which defines how fast the charge carriers move at a given field strength. In other words, it means how swiftly the charge carriers move through metals or semiconductors when dragged by the applied electric field. Based on films without and with electrodes, there are many ways to estimate the charge carrier mobilities.90 HerEquation (1)μ=8JL5Figure Due to their exceptional optoelectronic properties and excellent stability at standard operational conditions, Bi‐based PVKs have been used extensively for several optoelectronic applications including photovoltaics, photodetectors, memory devices, and capacitors. It provided a diverse structural platform for the novel nontoxic PVKs, where different A, B, and X‐site cations and anions have been exercised for numerous applications. Being A‐site organic cations, MA and Cs remained an essential part of the state‐of‐the‐art Pb‐based PVKs solar‐cells; therefore, as compared to the other A‐site cations, most of the Bi‐based PVKs are accompanied with MA and Cs as A‐site cations. Thus, in the first part of the succeeding section, some of the preliminary works based on the 0D Bi‐based PSCs (with Cs and MA as A‐site cations) will be conferred. Since high quality and compact Bi‐based PVK thin films remained a challenging issue for all the time; therefore, the ongoing discussion will be subdivided on the basis of numerous synthesis routes as well as solvent‐engineering and green solvents. In the next section, PSCs based on other types of Bi‐based PVKs will also be elaborated in detail. At the end of the section, a summary of the overall progress made on Bi‐based PSCs will be compiled. Moreover, optoelectronic applications other than PSCs will also be elucidated in detail, see a flowchart, 5.1 Owing to their comparable optoelectronic properties with Pb‐based PVKs, it is expected that Bi‐based PVKs could also provide the same solar‐cell characteristics. Therefore, followed by the pioneering effort of Park et al. in 2015, Bi‐based PVKs are rigorously exploited for photovoltaic applications.Undeniably, the hallmarked lead‐based PVKs are renowned for their unprecedently increased performance in solar‐cells.93 Owi three types of Bi‐based PVKs thin films, i.e., CBI, MBI, and MA3Bi2I9Clx have been synthesized via simple solution processability and spin‐coating. All these PVKs were prepared under ambient environmental conditions and their optical properties were studied that indicated long‐term stability. It was realized that like Pb‐based PVKs, the optical properties of Bi‐based PVKs also varied with the variation of the cations (MA or Cs), see Figure 5 cm−1 and their bandgaps and exciton binding energies were found to be in the range of 2.1–2.4 eV and 70–300 meV, respectively. Although their absorption coefficients were comparable to the conventional Pb‐based PVKs, their bandgaps and exciton binding energies were found to be way larger than Pb‐based PVKs. Finally, solar‐cells based on the above three PVK compounds were fabricated where the highest PCE of 1.09% was demonstrated by the CBI‐based device, see Figure  where a first single‐crystal and solution‐processed thin films of MBI were demonstrated for photovoltaic applications. The solar‐cell device exhibited a slightly higher PCE of 0.192% with open‐circuit voltage (VOC) of 0.51 V, short‐current density (JSC) of 1.16 mA cm−2, and fill factor (FF) of 46%. Likewise, Zhijie et al. synthesized a millimeter‐sized single crystal of A3Bi2I9 (A = methylammonium or MA and Cs) via a hydrothermal process. The prepared crystals exhibited a bandgap of 1.9 eV and spin‐coated thin films showed a uniform surface morphology, lower trap densities, significantly higher carrier mobility, and extended environmental stability. Finally, a solar‐cell device based on MBI PVK yielded a PCE of ≈0.2% with VOC 0.53 V, JSC 0.65 mA cm−2, and FF of 65%. Similarly, an air‐stable single crystal, powder, and thin films of MBI were synthesized and their optoelectronic properties were observed to be sensitive to the crystallinity of the compound. For instance, different bandgaps for a single crystal (1.96 eV) and thin film (2.26 eV) were observed. Additionally, an outstanding photocurrent generation in the visible range and longer exciton lifetime along with higher mobilities were revealed by transient absorption spectroscopy (TAS) and SCLC measurements, respectively. Unfortunately, a solar‐cell device underperformed with PCE of 0.11% along with VOC 0.72 V, JSC 0.49 mA cm−2, and FF of 31.8%, which was attributed to the poor film morphology. Subsequently, Oz et al. reported the preparation and structural properties of 0D MBI. The prepared PVK compound showed a relatively wider bandgap of 2.9 eV with a PL peak at 1.65 eV. The vibration modes of the bioctahedra [Bi2I9]3− were confirmed by their lower wavelength (>200 nm) Raman peaks, see Figure VOC of 0.66 V, JSC of 0.22 mA cm−2, and FF of 0.49%.In the preliminary work of Park et al.,55 thr A polycrystalline film was fabricated by a one‐step solution process and three types of device architectures, i.e., planar, on brookite meso‐TiO2, and anatase meso‐TiO2 were investigated. It was comprehended that the film morphology was significantly reliant on the choice of the substrate and device architecture. For instance, PVK films grew nonuniformly on the planar substrates; however, films grown on the anatase meso‐TiO2 layers exhibited better nucleation and uniform film growth, see Figure 2, the interparticle‐necking impeded the MBI percolation in the pores; thus, hindered the nucleation and uniform growth of the PVK film. Finally, solar‐cell devices fabricated on the anatase meso‐TiO2 exhibited better performance  than one fabricated on the brookite meso‐TiO2 layer, see Figure  synthesized MBI PVK through a one‐step solution process and systematically investigated the development of the film morphology on the meso‐TiO2/ITO surface. It was realized that the concentration of the precursor solution and the structure of the substrate were crucial for a highly crystalline PVK film. Consequently, the PCE of the solar‐cell was successfully improved to 0.42% with VOC 0.66 V, JSC 0.91 mA cm−2, and FF of 65%.In the aforementioned initial works, the PCE of MBI based solar‐cells was substantially lower  as compared to the CBI (with slightly higher PCE). There could be many reasons for the lower PCE including; poor film morphology and crystallinity, wider bandgap and deeper defect states, greater exciton binding energy, and material surrounding the active PVK layer, etc. Therefore, the effect of the electron transporting layer on the performance of MBI‐based solar‐cells was studied.99 A p3Bi2I10 was introduced, which exhibited an extended absorption spectrum with a relatively shorter bandgap (1.77 eV). In comparison with CBI, that new compound  exhibited a layered structure with different crystal orientations. Due to its broad OA spectrum, a solar‐cell made of Cs3Bi2I10 PVK showed an extended photocurrent up to 700 nm, which was possibly indicative of its increased optical absorption and photocurrent of the solar‐cell. Device characteristics showed a PCE of 0.4% with VOC 0.31 V, JSC 3.40 mA cm−2, and FF of 38%.A little modification in the stoichiometry of CBI was made and a new PVK compound, i.e., Cstroduced,101 wh5.2 Thus, it is challenging to fabricate compact thin films of Bi‐based PVKs. Therefore, along with conventional one‐step solution processability, many other techniques have been utilized to fabricate high‐quality Bi‐based PVKs thin films for improved PV device performance. Those techniques included: a) wet chemical approaches, including a single‐step and two‐step solution processability, b) dry routes, including vacuum vapor depositions or evaporation, magnetron sputtering, etc., c) other techniques based on the combination of dry and wet routes and electric field‐assisted spray coating, etc., as summarized in Figure The morphology of PVK thin film is crucial for superior PV performance. For instance, better crystallinity, full coverage of the substrate, and the vertically oriented (perpendicular to the substrate) PVK crystals are essential for the minimized shunt resistances, enhanced photoabsorption, and better charge transport. Unlike Pb‐based PVKs, Bi‐based PVKs crystalize directly in a rapid way without forming any intermediate solvated phases, which lead to isolated crystals instead of growing into a uniform pinholes‐free films.102 Th5.2.1 Therefore, the one‐step route was modified and vertically oriented MBI PVKs films were fabricated via a gas‐assisted one‐step solution process. The prepared thin films were found to be denser and smooth as compared with ones prepared with conventional 1‐step solution processability. Moreover, solar‐cell devices showed an improvement of ≈25% (from 0.548 to 0.686 V) in the open‐circuit voltage and 17% (from 0.070% to 0.082%) in the PCE, which was attributed to the lower charge recombination in the denser gas‐assisted PVK films. Similarly, Mali et al. studied the crystallization of the MBI PVKs (with a bandgap of 2.01 eV) prepared via an antisolvent strategy. Along with enhanced environmental stability, improved photovoltaic properties, i.e., PCE of 0.356% with VOC 0.653 V, JSC 1.10 mA cm−2, and FF of 54% were achieved, which were considerably higher than the ones prepared without antisolvent, see Figure The conventional one‐step solution process has been commonly adopted to fabricate PVK thin films with the following advantages: less time consumption, facileness, and cost‐effectiveness. However, due to the rapid crystallization of precursors, conventional one‐step solution processability lead toward certain disadvantages; including poor crystallinity, less coverage of the substrate, and the formation of noncompact and disoriented PVK films.98 The5.2.2 Furthermore, for some longer chain organic cations, it was difficult to find proper solvents. Conversely, the two‐step solution process overcame most of the above issues associated with a one‐step solution process, as reported previously for the Pb‐based PVKs. Therefore, uniform, smooth, and compact MBI films were synthesized via a novel two‐step evaporation‐spin‐coating technique . The excellent homogeneity and compactness of the pinholes‐free PVK film morphology further improved the optoelectronic properties of the solar‐cell device, e.g., PCE of 0.39% and a record open‐circuit voltage of 0.83 V were claimed. To make further advancement, a novel soaking‐assisted sequential two‐step method was introduced to fabricate highly uniform MBI thin films with superior coverage both on c‐TiO2 and m‐TiO2 substrates, as shown in Figure 3 films were first spin‐coated on the TiO2 substrates; which were successfully transformed (by dipping in MAI solution) into high‐quality MBI films. The effect of the improved morphology, as well as the device architecture on the performance of a solar‐cell was studied. It was realized that devices with m‐TiO2 showed better performance than the ones with planar structures. Along with excellent thermal and environmental stability, HTM‐free solar‐cell devices exhibited PCE of 0.054% with VOC 0.89 V, JSC 0.255 mA cm−2, and FF of 24%, see Figure Although the one‐step solution process was facile and cost‐effective but due to the rapid film crystallization, it lead toward nonuniform film morphology, more defects sites, the formation of pinholes, and less coverage of the substrate.98 FurVOC (0.72 V) was claimed. Similarly, the importance of MAI concentration in the precursor solution was realized when the MA3Bi2I9 compound was fabricated via interdiffusion of solution‐processed BiI3 and MA layers stacking on meso‐TiO2 substrate. In this method, BiI3 and MA films were first spin‐coated separately on the substrate and subsequently, the layers were converted into MBI PVK film via a solid‐state interdiffusion mechanism. At optimum concentrations, the film morphology, as well as the device performance was found to be superior to the ones fabricated via the conventional one‐step solution process, see Figure During film formation, the concentration of precursor and spinning speed play a vital role, which governs the crystal size and thickness of the PVK layer. For instance, at an optimum concentration of MAI in the precursor solution, the highest 5.2.33 and MAI) due to a subsequent encounter with commonly used corrosive solvents. Therefore, a solvent contact‐free two‐step solid‐state approach was adopted; where BiI3 film was first deposited on the TiO2 via a high vacuum evaporator and subsequently transformed into a high‐quality MBI film in the MAI thermal atmosphere for 6–10 h, see Equation  is a powerful route to fabricate high‐quality thin film and has been extensively applied for the iconic Pb‐based PVK thin films.114 Th Therein first, the Cu–Bi alloy was sputtered on the ITO‐substrate and subsequently exposed to the vaporous I2 in a sealed container under a nitrogen atmosphere for 10 h, which yielded a highly oriented blackish‐gray film with a bandgap of 1.81 eV. Apart from these, comparable photoelectric characteristics with MAPbI3 were revealed by photoinduced carrier dynamics. Finally, a solar‐cell device demonstrated a PCE of ≈1.12%, VOC 0.37 V, JSC 7.18 mA cm−2, and FF of 28%, which was claimed to be the highest PV performance for CuBiI4. Similar PVK compounds with Ag instead of Cu  were fabricated via simple solution processability by Shao et al. that showed a maximum PCE of 0.78%.In comparison with other conventional solid‐state routes, the reaction was extremely fast, occurred at lower temperatures (80 °C) and ambient conditions. Finally, solar‐cell devices prepared by this method showed comparable performance with ones fabricated via conventional solution processability. This method provided certain advantages over the others; for example, less time consumption and large‐area device fabrication.106 Th5.2.4 In the solvent‐engineering technique, a less volatile solvent  was combined with the highly volatile solvent . As a result, the quality of PVK thin film was improved, i.e., it first formed a PbI2·DMSO complexes, which was converted into high‐quality PVK crystals by subsequent annealing. Therefore, the state‐of‐the‐art PSCs with PCE > 20% are mostly fabricated through solvent‐engineering and antisolvent techniques. In these techniques, an antisolvent, e.g., toluene, chlorobenzene, or chloroform, etc. was poured immediately on the already spinning PVK film. As a result, the solubility of the solute was reduced and the supersaturation condition was achieved, which accelerated the nucleation process and lead toward smaller grain size and high‐quality uniform film. Therefore, Shin et al. utilized both of the above strategies to fabricate high‐quality PVK thin films of MBI and FA3Bi2I9 (FBI). In order to do that, either DMSO or butylpyridine (tBP) was combined with DMF and were used as a solvent to form bismuth complexes. It was realized that by increasing the solubility of BiI3, and suppressing the rapid evaporations of the solvents; the Bi‐complexes promoted the supersaturation during spinning, which lead toward highly compact PVK films, as shown in Figure VOC 0.85 V, and FF of 73%.One of the reasons for the poor PVK film quality was the rapid evaporation of the highly volatile solvents, e.g., dimethylformamide (DMF), which was commonly exercised for the synthesis of PVK precursors. Solvent‐engineering is still a promising way to suppress the rapid evaporation of highly volatile solvents. This technique has been utilized successfully for the fabrication of high‐quality Pb‐based PVK films.116 InN‐methyl‐2pyrrolidone (NMP) was added into the precursor solution of MBI (in DMF). After the analysis of various concentrations in the precursor solution of MBI, NMP was realized as a morphology controller that governed the crystal growth of MBI film. With the optimized amount of NMP (25 mL) in the precursor solution, the JSC of a solar‐cell was successfully improved by 50% as compared with devices prepared without NMP. Along with enhanced environmental stability and high reproducibility, the solar‐cell devices yielded a PCE of 0.31% with VOC 0.51 V, JSC 0.94 mA cm−2, and FF of 61%.Similarly, a minute amount of (in DMF).119 Af3Bi2I10 films with bandgaps of 2.08 and 1.80 eV, respectively. Therein, an antisolvent dripped film was annealed under the DMF vaporous atmosphere to prevent the rapid evaporation of the DMF from the precursor, which lead toward a homogenous and pinhole‐free PVK films. Moreover, interfacial engineering was also applied to eliminate the interface band‐offset by utilizing PTAA and NiOx as hole transporting layers (HTLs). Consequently, a solar‐cell made of CBI (with NiOx as HTL) demonstrated better PV performance, i.e., a PCE of 1.26% with VOC 0.61 V, JSC 1.12 mA cm−2, and FF of 43%. The improved PV performance was attributed to the better film morphology, elimination of band offset, and control over the leftover metal contents in the film. Similarly, ultrathin all inorganic CBI nanosheets were fabricated via the dissolution recrystallization process. It was revealed by scanning electron and atomic force microscopy that nanosheets formed a uniform and compact thin film with a lower surface roughness of 4.3 nm, which could be beneficial for better contact with charge transporting layer. Consequently, along with better environmental stability, a solar‐cell device demonstrated a significantly higher PCE of 3.20% along with VOC 0.86 V, JSC 5.78 mA cm−2, and FF of 64.38%. Up to the best of our knowledge, it was the highest PCE ever reported for the 0D Bi‐based PVKs.Besides the aforementioned film fabrication techniques, other techniques were also applied. For instance, a solvent annealing technique was applied to fabricate larger grain‐sized, compact CBI and Csectively.120 ThFrom the above discussion, it can be concluded that compositional and interfacial engineering along with antisolvent dripping is the most promising way, which is not only cost‐effective and facile but also less time consuming for the fabrication of high‐quality Bi‐based PVK films and high‐performance PV devices.5.3 successfully synthesized the MBI perovskite compound in the green solvent, i.e., ethanol. As compared with the typical toxic organic solvents (DMF and DMSO), MA‐BiI3 complexes showed a higher solubility in ethanol; therefore, PVK films showed a denser and homogenous morphology. Consequently, enhanced photovoltaic properties, i.e., a PCE of 0.022% with significantly improved open‐circuit voltage of 0.84 V and JSC 0.17 mA cm−2 were obtained. Similarly, methyl acetate was used as a nontoxic solvent for the lead‐free MBI PVK and high‐quality uniform thin films were fabricated on meso‐TiO2 for solar‐cell applications. After fine‐tuning of the HTL, a solar‐cell device yielded a PCE of 1.62% under 1 sun illumination. Moreover, a solar‐cell device demonstrated an enhanced photostability of 300 h under 1 sun illumination without any UV shutter.In addition to Pb, the consumption of less volatile toxic organic solvents  in large amount are also hazardous for humans and their environment. Therefore, Li et al.122 su5.43Bi2X9 PVKs was their lower dimensionality, which rendered them to high exciton binding energy, shorter carrier lifetime, higher charge trapping density, and lower charge carrier mobilities. Indeed, the higher charge of Bi3+ made it harder to adapt a typical 3D‐PVK structure . In order to incorporate Bi3+ into PVK framework such that it maintains a 3D structure, a class of quaternary (A2M+M3+X6) PVKs known as “elpasolites” or “double PVKs” was introduced, which could extend the conventional 0D A3Bi2X9 PVKs into 3D ones, unaffecting the total number of valence electrons. Initially, several double PVK compounds with numerous combinations of M+ and M3+ metal cations were suggested. Although after many theoretical studies, it was realized that only compounds with proper enthalpy, energy bandgap, exciton binding energy, and carrier effective masses could be utilized for PV applications. Among those PVKs, Cs2BiAgBr6 was suggested to be the most suitable one for PV applications due to its extraordinary properties including, lower bandgap, higher stability, extended carrier lifetime, and comparable carrier effective masses. Despite these remarkable properties, the lower solubility of Cs2BiAgBr6 precursors was hindering it to form a compact and uniform PVK thin films; until an effort was made by Greul et al. to fabricate Cs2BiAgBr6 thin films and utilized them successfully into a working solar‐cell device. After optimization, a solar‐cell device showed a considerable PCE of 2.5% with a significantly high open‐circuit voltage of over 1 V, which was claimed to be the highest VOC to date for any Bi‐based PVK solar‐cell. Moreover, the solar‐cell device showed improved stability in operational conditions. Subsequently, a first lead‐free heterojunction PVK solar‐cell composed of high‐quality double‐PVK  was fabricated through a low pressure‐assisted solution process in an ambient environment. It was observed that the annealing temperature had a pronounced effect on the film quality, i.e., the film quality was significantly improved when the temperature varied from 150 to 300 °C. Finally, an unencapsulated device not only showed better resistance to the ambient environment but also exhibited an improved PV performance, i.e., a PCE of 1.44% along with VOC 0.99 V, JSC 1.79 mA cm−2 and FF of 65%. Recently, the same double PVK was utilized into a planar heterojunction solar‐cell and achieved a significantly improved PCE of 2.23% with VOC 1.10 V, JSC 3.19 mA cm−2 and FF of 69.2%, see Figure 2AgBiBr6, Zhang et al. introduced another novel double PVK, i.e., Cs2BiNaI6 via a hydrothermal process. The proposed PVK compound showed a relatively smaller bandgap of 1.66 eV; however, besides improved environmental stability, a solar‐cell device made of this PVK compound delivered poor performance, i.e., PCE of 0.42% with VOC 0.47 V, JSC 1.99 mA cm−2 and FF of 44%.One of the reasons for the poor PV performance of 0D A., ABX3).43 In  and iii) the inclusion of the monovalent cation that restricted the combination of different A and B‐site cations to achieve the desired PV properties.Although in comparison with 0D MBI PVKs, its 3D‐counterparts  demonstrated some improvement in the PCE along with better short‐term stability, still their PCE could not exceed over 2.5%. The possible reasons for this lower PV performance could be: i) a wider and indirect energy bandgap , ii) the presence of Ag, which was degraded after long term exposure to ambient conditions,124a a6 was studied. Such a novel structure provided a possibility of a vast combination of A‐site cations and tunable bandgaps. For instance, a double PVK with triple A‐site cations, i.e., KBaTeBiI6 with an optical bandgap of 1.88 eV was reported by Thind et al. The proposed structure was first modeled theoretically and afterward, it was fabricated via a wet chemical approach. It was realized that the effective masses of the charge carriers were comparable to those of the best performance Bi‐based double PVKs materials. Along with better environmental stability, a solar‐cell device exhibited PCE of 0.057% with VOC 0.54 V, JSC 0.09 mA cm−2 and FF of 58%. The poor PV performance of a device was attributed to the stoichiometric and structural defects.To address these issues and establish a stable 3D Bi‐based PVK framework with lower bandgap, a family of double PVK oxides with general formula A′A″B′BiOnd et al.129 Th5.5 Therefore, silver bismuth iodide compounds with various stoichiometries, i.e., AaBbXx (with x = a + 3b) were introduced. This family  was named as “Rudorffites;” after Walter Rudorff, the discoverer of the similar prototype oxides, i.e., NaVO2.Among various families of Bi‐based PVKs, the silver bismuth iodide based PVKs showed a suitable bandgap (1.62–1.8 eV) for the PV applications.131 Th2I7 with pure cubic structure  analysis) was presented by Kim et al. The solution‐processed spin‐coated film of AgBi2I7 exhibited a dense pinhole‐free morphology and a relatively lower bandgap of 1.87 eV, suitable for photovoltaic applications. Moreover, it was observed that the phase‐pure cubic AgBi2I7 compound can only be obtained at temperatures > 110 °C, as shown in Figure VOC 0.56 V, JSC 3.30 mA cm−2, and FF of 67.41%, which was well preserved for 10 days in the ambient environment, see Figure 2I7) with a hexagonal structure and indirect (1.62 eV) and direct (1.85 eV) bandgaps were also reported. A photocurrent in a broad range of EM‐spectrum  with a maximum external quantum yield of 45% was recorded. Furthermore, solar‐cells made of this PVK material yielded an improved photovoltaic performance, i.e., a PCE of 2.1% with VOC 0.49 V, JSC 6.8 mA cm−2. Likewise, a step toward further improvement in the performance of Rudorffites‐based PSCs was taken by Turkevych et al. and introduced the same compound (AgBi2I7 with cubic structure) along with other silver bismuth iodides PVKs . A solar‐cell device with configuration (FTO/c‐m‐TiO2/Ag3BiI6/PTAA/Au) demonstrated significantly improved PCE of 4.3% along with VOC 0.63 V, JSC 10.7 mA cm−2, and FF of 64%. This was the best PV performance to date exhibited by any Bi‐based PVK solar‐cell. Successively, a Rudorffite compound, i.e., Ag2BiI5 with various BiI3 to AgI ratios was synthesized by solid‐state reaction. A solar‐cell device with pure Ag2BiI5 exhibited PCE of 1.74% whereas a device with an excessive amount of BiI3 (as an impurity) yielded significantly improved PV‐characteristics, i.e., a PCE of 2.31%, VOC 0.594 V, JSC 4.20 mA cm−2, and FF of 54.8%. Moreover, along with negligible hysteresis, a solar‐cell device showed a long‐term resistance to environmental influences. It is to be noted that even though Turkevych et al. and Jung et al. achieved a considerably improved PCE along with better stability, their synthesis routes were very expensive in terms of temperature (>500 °C) and time‐consumption; therefore, could not be applied on large scale. Recently, a two‐step coevaporation or annealing technique was utilized to fabricate thin films of AgBiI4, Ag2BiI5, and Ag2BiI7 with improved surface morphology and larger crystal size (>3 µm). A solar‐cell device based on these compounds demonstrated a relatively lower PCE of 0.9% and improved VOC of > 0.8 V. Unfortunately, along with underperformed PCE, a solar‐cell device displayed a significantly larger hysteresis loss, which could be attributed to the higher defects concentration in the material.A first PV application of the silver bismuth iodide PVK compound, i.e., AgBi One way to fabricate thin films with larger grain size is hot casting, i.e., spinning or pouring the PVK precursor solution on a hot substrate. Therefore, Gosh et al. utilized a dynamic hot‐casting technique to fabricate complex 3D analogs of ternary bismuth halide PVKs  and achieved compact PVK films with considerably large grain sizes. Solar cells with mesoscopic architectures were fabricated in the ambient environment (RH  ≥  65%), which yielded a record PCE  among all solution‐processed Bi‐based PVKs. It should be noted that Turkevych et al. reported a PCE of 4.3% for the similar PVK (AgBiI6) but that was synthesized via expensive solid‐state routes with processing temperature higher than 500 °C.The grain size for the PVK film is a critical parameter that governs the PV performance of a device. For instance, a direct relationship between the size of the PVK crystal and photocurrent was reported.133 On5.6 introduced a corrugated 1D hybrid organic–inorganic Bi‐based n‐type PVK compound  with an optical bandgap of ≈2.1 eV. A photoelectrochemical analysis revealed that HDABiI5 based devices demonstrated a steady‐state short‐circuit current density of ≈100 µA cm−2 along with a stable VOC of 400 mV under 1 sun illumination. Furthermore, along with better stability, a solar‐cell device made of such a PVK compound exhibited a PCE of 0.027% with VOC 0.43 V and JSC 0.124 mA cm−2.In addition to the above Bi‐based compounds where MA, Cs, FA, and Ag were used as A‐site cations, structures with new organic cations were also applied for improved PV performance. For example, Fabian et al.46 int5H6NBiI4 and C6H8NBiI4) with a bandgap of 2.0 eV and 1D structure (formed by edge‐shared octahedra) were reported. It was revealed by density functional theory (DFT) calculations that the organic entities in the structure promoted the intermolecular interaction, which supported the ability of pseudo‐3D charge transport due to matching energies with the conduction band minima. Along with better environmental stability, a solar‐cell device (without HTL) yielded a PCE of 0.9% with VOC 0.62 V, JSC 2.71 mA cm−2, and FF of 54%. Apart from this, three novel organic–inorganic Bi‐based PVKs, i.e., (C3H4NS)3Bi2I9, (C3H4N2)3Bi2I9, and (C3H5N2S)BiI4, were introduced. The first two PVKs were found to be 0D while the third one was 1D with optical bandgaps of 2.08, 2.0, and 1.78 eV, respectively. Among these PVKs, the best performance solar‐cell based on (C3H5N2S)BiI4 delivered a PCE of 0.47%.Similarly, two novel organic–inorganic Bi‐based PVKs  exhibited better PV performance among the other Bi‐based PVKs, still their PCE was far lower. The reason for this lower PCE was their wide bandgap and downshifted valence band edges. To address these issues, a sulfide dianion was utilized as an anionic substitute, which successfully altered the optoelectronic properties of AgaBibIa+3b based PVKs. With this strategy, the energy bandgap was successfully narrowed by 0.1 eV where the valence band edge was lifted up by 0.1–0.3 eV in the different stoichiometries of silver bismuth iodides . Solar‐cell devices based on these silver bismuth sulfoiodides presented a remarkable improvement in the device performance and PCE was boosted up to more than 5.44%, along with VOC = 0.57 V, JSC 14.6 ± 0.1 mA cm−2, and FF of 66%, see Figure 2 nanocrystals (dispersible in most of the organic solvents) were synthesized via the hot‐injection method. The nanocrystals exhibited a strong absorption with absorption coefficient ≈103–105 cm−1, a suitable bandgap of 1.3 eV, and excellent environmental stability. Finally, the optimized device based on tetramethylammonium iodide (TMAI)‐treated AgBiS2 solar‐cells demonstrated the best performance with a PTB7 as an HTL and yielded a certified PCE of 6.3%. To the best of our knowledge, this is the highest PCE reported for any Bi‐based PSCs yet.Although silver bismuth iodides AgaBibIa+3b exhi1−xBixSI where halides and chalcogenides coexisted. The alloyed compound exhibited a bandgap of 1.62 eV, which was suitable for photovoltaic applications. Under standard illuminations, a solar‐cell device based on this compound exhibited a better PCE of 4.07%, which was retained up to 92% under standard conditions with a relative humidity of 60% and a temperature of 85 °C for 360 h. It is important to note that the SbSI compound (without Bi) with a bandgap of 2.1 eV was previously used for PV application where a PCE of 3.05% was recorded. Similarly, another novel PVK compound  based on the halide‐chalcogenides combination was reported, which exhibited even a lower bandgap of 1.52 eV, more suitable for the PV devices. Yet, a solar‐cell device made of this compound showed a relatively lower PCE of 0.13%.Additionally, Bi is also used in a combination with other lower‐dimensional material to form alloyed structures and enhance PV performance. For instance, it was combined with quasi‐1D SbSI to form an alloyed compound, i.e., Sb5.83 and BiMnO5). A considerable PCE of 4.2% along with VOC 1.48 V, JSC 7.03 mA cm−2, and FF of 58% was obtained under 1 sun illumination. It was understood that instead of the interior of the crystal grains, the photocurrent was developed at the grain boundaries. Moreover, the VOC and JSC were found to be governed by the resistance of the device, hence showed the multifunctionality of the photovoltaic device. It is noteworthy that unlike the above work, the performance of the semiconducting devices usually deteriorates upon turning the material from a single crystal to polycrystalline. However, as a benefit of the combination of the two oxide phases, it was recognized that the resultant VOC was greater than that of the individual compounds, hence high‐performance solar‐cell device was obtained.Besides, being a B‐site element of the PVK architecture, Bi has also been utilized at A‐site along with other similar materials. For instance, it was used with Mn (at the A‐site of the PVK framework) to fabricate a multifunctional PV device based on the composite of the mixed phases (BiMnO BiMnO5).142 A TableFigure From all of the above discussion about the photovoltaic applications of the Bi‐based PVKs, it can be concluded that better film morphology, lower energy bandgap, and minimum energy band offset (between the active layer and HTM) could enable the Bi‐based PSCs to achieve an enhanced PCE and better environmental stability. So far, these requirements are mostly fulfilled by the strategy of alloying or doping of other lower bandgap material  with Bi; boosted the PCE above 6.3%, which was under 4% for the phase‐pure Bi‐based PSCs. The overall progress of the reported Bi‐based PSCs is summarized in 6Due to their favorable photoabsorption, Bi‐based PVKs are mostly exploited for photovoltaics; although they have also been utilized for other optoelectronic applications, e.g., photodetectors, capacitors, and memory devices, which are discussed in the following section.6.1 The first CsBi3I10‐based photodetector was fabricated in 2017 by Tong et al., see Figure 5 along with a rapid response speed of τrise = 0.33 ms and τdecay = 0.38 ms. The photodetector exhibited a specific detectivity of 21.8 A W−1 and photoresponsivity (ratio of current to incident light) of 1.93 × 1013 jones, which was superior to the Pb‐based photodetectors. Moreover, the device demonstrated a high external quantum efficiency of 4.13 × 103% along with outstanding environmental stability for more than 3 months in the ambient air.Photodetectors are PV devices that absorb photons and convert them instantly into electrical impulses. Photodetectors have got a key role in communications, remote sensing, biological and chemical sensing, computation, and imaging, etc. Due to higher absorption coefficients, Bi‐based PVKs can absorb light efficiently even if the film is a few hundred nanometers thick. Owing to confinement in such a small region, the charge carriers could not travel up to larger distances; therefore, the charge collecting electrodes should be closed enough to ensure faster carrier transport and photoresponse. Recently, Bi‐based PVKs were employed successfully for photodetection purposes.143 Th5 with dimensions of 32 × 24 × 12 mm3 was fabricated. The photodetecting device showed an excellent performance with an on/off ratio of ≈103 and a rapid response speed of τrise = 8.9 ms and τdecay = 10.2 ms. Moreover, the photoresponsivity of the device was measured to be 100 mA W−1, which was almost invariant in the 365–700 nm range, see Figure 3Bi2I9 nanoplates was fabricated by Qi et al. Such a device was directly fabricated via facile solution processability on the ITO glass substrates and could also be deposited on any sort of substrate. This was the first photodetector based on CBIPVK with photoresponsivity of 33.1 mA W−1 under an illumination laser beam of 450 nm wavelength. The photoresponse of these devices was surprisingly 6‐times higher than the solution‐processed photodetectors based on MAPbI3 nanowires. Along with better operational stability, the specific detectivity of the device was observed to reach values as high as 1010 jones. Moreover, τrise and τdecay were recorded to be 10.2 and 37.2 ms, respectively.Similarly, a photodetector based on highly oriented single crystals of TMHDBiBrbricated.143c T2Bi2I10·2H2O was reported. The photodetecting device exhibited relatively lower performance, i.e., a photocurrent of 194 mA with an on/off ratio of 2.1 and photoresponsivity of 1.14 mA W−1. In addition to this, the device also exhibited lower specific detectivity of 1.9 × 106 jones and an external quantum yield of only 0.4%. Similar underperformed photodetectors were also fabricated from 1D and 2D PVK compounds, i.e., (C6H13N)2BiI5, (TMP)BiX5 , and 2D‐PVK, i.e., (TMP)1.5[Bi2I7Cl2], see Figure Recently, another photodetector based on vertically oriented single crystals of 0D PVK‐like material, i.e., (PD)reported.143e T6.2 Such ultrathin memristors demonstrated a typical resistive‐switching behavior at a lower operating voltage of ≈0.3 V, remarkably higher ON/OF ratio ≈103, and extended data retention of >104 s. Additionally, the memory devices exhibited excellent environmental durability, flexibility, reproducibility, and endurability, see Figure 4 s, and 300 cycles endurance was reported. The device showed a multilevel data storage capability with four resistive states and retained its properties for more than 5 months in the ambient environment.Other than the aforementioned optoelectronic applications, Bi‐based PVKs are also utilized for the resistive memory storage devices, i.e., memristors. The first flexible memristors based on the nanosheets of CBI and MBI were fabricated via the dissolution and recrystallization process.144 Su reported a double‐layered electrochemical capacitor of MBI thin film. A maximum capacitance of 5.5 mF cm−2 was demonstrated by the device and retained well up to 84.4% even after 10 000 charging–discharging cycles, see Figure Along with memristors, Bi‐based PVKs were also exploited for the fabrication of ultrafast capacitors. For instance, Pious et al.146 re7 numerous Bi‐based PVKs have been introduced and exploited for various optoelectronic and photovoltaic applications. However, the PCE of these compounds is on the lower side with a maximum of 6.3% reported for AgBiS2, while PCEs above 3% are rarely reported.Albeit the hallmarked Pb‐based PSCs have reached the summit of 25.2% PCE, its toxicity is still a major concern about its industrialization. Amongst the nontoxic alternatives, Bi‐based PSCs have shown promise, yielding outstanding environmental stability and optoelectronic properties, which are at par with the Pb‐based PVKs. After the pioneering work of Park et al.,55 num7.1a)Improving film morphology: The quality of Bi‐based PVK films could be improved by pursuing the prevailing fabrication techniques, which are already utilized successfully for the Pb‐based PVK films. For instance, the morphology of the Bi‐based PVK films fabricated via a two‐step wet‐solution process was found to be superior to the ones prepared via a single‐step wet‐solution process. Likewise, the film quality was further improved when the dry and wet routes were combined. The film quality can be further improved with i) optimization of the precursor solution, ii) solvent‐engineering to decrease the volatility of the precursor solutions and their rapid crystallization, iii) use of antisolvent at the time of film fabrications, and iv) the introduction of the cost‐friendly novel solid‐state routes which have the potential for the fabrication of large‐area PVK films in the ambient environment.b) see Figure  However, the exertion of such a high external pressure  on the operating photovoltaic devices is not viable; therefore, an alternative way is to apply chemical pressure as previously done for the Pb‐based PVKs. Another strategy could be the fabrication of composites by the addition of materials with relatively lower bandgaps. Furthermore, the utilization of different experimental tools and theoretical calculations are required to explore the numerous possible combinations of the Bi‐based double PVKs, which could provide 3D Bi‐based PVK compounds with lower energy and direct bandgaps, suitable for optoelectronic applications.Tuning the bandgap: It has been shown that external pressure can help to decrease the bandgap in the Bi‐based PVK crystals,147 sec)3Bi2X9) is the main reason for their high exciton binding energy, shorter carrier lifetime, higher charge trapping density, and lower charge carrier mobilities. This issue could be addressed by Bi‐based double PVKs; unfortunately, out of their numerous combinations, only a few of them are explored yet. Detailed theoretical calculations are needed for the exploration of new double PVK compounds based on various combinations of M+ and M3+ with appropriate enthalpy, energy bandgap, exciton binding energy, and carrier effective masses. Additionally, it is reported that double PVKs show lower solubility in the conventional organic solvents; therefore, instead of borrowing the solvents from the Pb‐based PVKs, a hunt for new suitable solvents is vital.Increasing the dimensionality: The lower dimensionality of Bi‐based PVKs  and spiro‐OMeTAD (5.13 eV). Therefore, novel hole‐transporting materials (HTMs) with minimum energy band offset are required to ensure better charge transport and high open‐circuit voltage. Moreover, the PCE could further be improved by a) the partial inclusion of Pb with Bi could fabricate synergetic PV devices with better performance and lower toxicity and b) surface passivation by utilizing suitable ligands.Further enhancement in the efficiency can be achieved by designing novel device architectures different from the existing Pb‐based PSC. Owing to their comparatively deeper valence band maxima, there existed a larger bandgap mismatch between HTL and active PVK layer; for instance, between Cs5.13 eV).126 Th7.2) is required to analyze the exact stability of the Bi‐based PVKs.The following strategies can be used to further uplift the environmental stability of the Bi‐based PVKs: a) implanting inorganic or hydrophobic organic cations to improve their moisture stability, b) utilizing the metal nanoparticles to downconvert the high energy UV‐light into a visible lower energy radiations to improve their photostability, and c) employment of thermal‐resistive transparent 2D‐material on top of active material to increase the thermal stability of devices. Moreover, the stability could be improved further by surface modifications using certain additives; for example, ionic liquids and other moieties. Although the stability of the Bi‐based devices is reported to be better than the Pb‐based ones, still there is no detailed study been done to measure their stability in the controlled humidity, temperature, and light. Therefore, a standard testing procedure  i7.3 Due to thermal and photoinstability, the conventional Pb‐based PVKs cannot be used as a top layer in the tandem cells. Besides PV applications, Bi‐based PVK exhibited excellent performance (even better than Pb‐based PVKs) with extended stability in other optoelectronic applications; for instance, photodetectors, memristors, and capacitors. Unfortunately, there are only a few reports on such devices; therefore, extensive scrutiny is required to explore the potential of Bi‐based PVKs in optoelectronic applications other than solar‐cells. Similarly, there are few reports on the highly stable and more efficient inorganic Bi‐based perovskites ; therefore, a substantial effort is required for both material synthesis and device fabrication of the inorganic Bi‐based PVKs to utilize them for the optoelectronic applications. Moreover, the ambient environment processing of inorganic Bi‐based optoelectronic devices could significantly decrease the fabrication price.Bi‐based PVKs are nontoxic, highly stable, and possess excellent optoelectronic properties. The wider bandgap of phase‐pure undoped Bi‐based PVKs is nearer to the optimum bandgap of the top cell in Si‐based tandem cells , where Bi‐based alloyed PVKs exhibited a smaller bandgap closed to the optimum bandgap of the single‐junction solar‐cell.151 DuDue to the aforementioned advantages, we conclude that Bi‐based PVKs have the potential to substitute the toxic Pb in various next‐generation optoelectronic devices. However, Bi‐based PVKs are still in the stage of material development and a collaborative multidisciplinary effort is required from researchers to understand their structural, optical, and electronic properties to effectively exploit them for various optoelectronic applications.The authors declare no conflict of interest.


Vascular calcification (VC) is commonly associated with bone loss in patients with chronic kidney disease (CKD). The Wingless-related integration site (Wnt) regulates osteoblast activation through canonical signaling pathways, but the common pathophysiology of these pathways during VC and bone loss has not been identified. A rat model of adenine-induced CKD with VC was used in this study. The rats were fed 0.75% adenine  with or without intraperitoneal injection of calcitriol (0.08 µg/kg/day) for 4 weeks. Angiotensin II (3 µM)-induced VC was achieved in high phosphate medium (3 mM) through its effect on vascular smooth muscle cells (VSMCs). In an mRNA profiler polymerase chain reaction assay of the Wnt signaling pathway, secreted frizzled-related protein 5 (sFRP5) levels were significantly decreased in the CKD rat model compared with the control group. The repression of sFRP5 on VSMC trans-differentiation was mediated through Rho/Rho-associated coiled coil containing protein kinase (ROCK) and c-Jun N-terminal kinase (JNK) pathways activated by Wnt3a. In a proof of concept study conducted with patients with CKD, serum sFRP5 concentrations were significantly lower in subjects with VC than in those without VC. Our findings suggest that repression of sFRP5 is associated with VC in the CKD environment via activation of the noncanonical Wnt pathway, and thus that sFRP5 might be a novel therapeutic target for VC in CKD. Chronic kidney disease mineral and bone disorder (CKD-MBD) is a common complication and among the important contributors to cardiovascular mortality in patients with CKD ,2. AbnorThe Wingless-related integration site (Wnt) signaling pathway is considered to be a critical component of the regulation of bone formation and resorption, and study of this pathway has increased our understanding of the pathophysiology of CKD-MBD. In particular, the canonical Wnt/β-catenin signaling pathway has been of great interest in bone research ,7, as itThe Wnt signaling pathway has also been shown to be involved in the pathogenesis of VC , which mIn this study, we attempted to identify changes in the Wnt signaling system in the context of CKD with VC. We explored the gene expression profile of the Wnt signaling pathway in an animal model of CKD to investigate how regulation of this pathway is altered as VC progresses in CKD. We also identified a candidate for the main regulator of Wnt signaling leading to VC.To induce CKD with VC, rats were fed a specially formulated adenine diet for 4 weeks. A subset of rats also received intraperitoneal (IP) injections of calcitriol (0.08 ug/kg) daily . The kid2-profiler polymerase chain reaction (PCR) array, is provided in To explore how Wnt signaling regulation is altered during the progression of VC in CKD, we explored the gene expression profile of Wnt signaling pathway molecules in the animal model of CKD with VC. Among the 84 genes studied, 13 showed significantly different expression between the CKD with VC and control groups . SecreteBased on the RNA profile and PCR array, we investigated sFRP5 regulation in CKD with VC in vitro. Vascular smooth muscle cells (VSMCs) were treated with angiotensin II and vitamin D in high phosphate medium (VC induction medium) to mimic the CKD with VC environment. Osteoblastic differentiation of VSMCs was demonstrated by elevated expression of the osteoblast marker Runt-related transcription factor 2 (RUNX2) and decreased expression of the smooth muscle lineage marker α–smooth muscle actin α-SMA; . All sFRTo explore the functional role of sFRP5 in VC, we induced trans-differentiation of VSMCs via VC induction, added sFRP5, and evaluated the degree of VSMC trans-differentiation. Treatment of VSMCs with sFRP5 in VC induction medium decreased the expression of RUNX2, and neutralization with anti-SFRP5 attenuated the effect of sFRP5 on RUNX2 expression A. In addWe next assessed the role of the noncanonical Wnt signaling pathway in the protective effect of sFRP5 against VSMC calcification. Rho-associated coiled coil containing protein kinase-2 (ROCK-2) and phosphorylation of c-Jun N-terminal kinase (JNK), downstream targets of the noncanonical Wnt signaling pathway, were increased in VSMCs incubated in VC induction medium . The addThe noncanonical Wnt/planar cell polarity signaling pathway is believed to activate ROCK and JNK through the activation of Rho and Rac, respectively ,20. HowePrevious studies have shown that sFRP5 antagonizes Wnt5a-mediated noncanonical signaling ,23,24. HWe next performed an in vivo study using a rat model of adenine-induced CKD to verify the findings of our in vitro studies. The expression of RUNX2, an osteoblastic marker, was significantly increased in the CKD and CKD with VC groups compared with the control groups . VC was p < 0.01; p < 0.01). The baseline characteristics of the subjects, including sFRP5 serum levels, are shown in To investigate whether sFRP5 regulation is relevant for VC in humans, we measured the serum concentrations of sFRP5 in human subjects with normal renal function and in patients on hemodialysis (HD) due to CKD. The serum concentration of sFRP5 was significantly lower in subjects on HD than in those with normal renal function  are known to be endogenous inhibitors of the Wnt signal transduction pathway ,36. sFRPOur finding of decreased Wnt5a expression during the induction of VC in CKD may be explained by Wnt5a’s regulation of two distinct Wnt signaling pathways. Wnt5a has been shown to inhibit the canonical Wnt signaling pathway and activate the noncanonical Wnt signaling pathway ,45. In oThe exposure of VSMCs to a uremic milieu resulted in sFRP4 protein overexpression. Our in vivo study yielded similar results, as the induction of CKD and VC increased sFRP4 protein expression, but not mRNA levels. These results are consistent with those of previous studies showing that sFRP4 is involved in renal phosphate wasting with fibroblast growth factor-23 . The sigIn this study, we found that serum sFRP5 levels were lower in patients with VC. sFRP5 was found to be highly expressed in retinal pigment epithelial cells and in the pancreas . sFRP5 eRecent reports claim that even single ischemic events such as myocardial infarction can alter the transcript of blood vessels and play an important role in VSMC remodeling ,53,54. IConsidering the purpose of this study, it is important to discern which Wnt signaling system simultaneously affects VC and bone health. Although we detected an increase in β-catenin expression in our model, we found no other indicator of canonical pathway activation. Thus, in subsequent research we will seek to determine how sFRP5 influences canonical Wnt signaling and conduct a more detailed analysis of the pathway components.In summary, our study showed that the reduction of the sFRP5 level in an animal model of adenine-induced CKD with VC was associated with the activation of the noncanonical Wnt pathway. In addition, sFRP5 had an inhibitory effect on VSMC trans-differentiation into osteoblast-like cells, which is also involved in the regulation of the Wnt3a-mediated noncanonical signaling pathway through the inhibition of Rho/ROCK/JNK signaling . We alsoHuman aortic VSMCs were obtained from Lonza Inc.  and grown for six passages in SmGM-2 BulleKit culture medium . VSMCs were then transferred to Dulbecco’s modified Eagle’s medium and treated with phosphate to obtain a final phosphate concentration of 3 mM. Angiotensin II  and calcitriol  were added and the cells were incubated for 14 days to induce calcification.Male Sprague Dawley rats were purchased from Orient Bio . The animals were kept in a light- and temperature-controlled room with free access to chow and deionized water. All animal experiments were performed with the approval of the Institutional Animal Care and Use Committee of Gachon University (LCDI-2018-0136 on 19 December 2018), and in accordance with the Guidelines for Animal Care and Use of the Gachon University Lee Gil Ya Cancer and Diabetes Institute. 2D3, calcitriol  were administrated daily. As the adenine diet alone is unlikely to induce VC [To induce CKD with VC, rats were fed a specially formulated adenine diet for 4 weeks, in a modified version of a previously described adenine model . The adenduce VC ,57, an anduce VC ,59. RatsAll animals were euthanized 4 weeks after initiation of these diets. Under isoflurane anesthesia, blood samples were collected from the abdominal aorta, and the thoracic aorta was extracted for the analysis of VC and gene expression.The rats’ thoracic aortas were fixed in 4% paraformaldehyde and embedded in paraffin blocks. The sections were stained for VC using von Kossa’s method. Briefly, the sections were deparaffinized and washed with distilled water. They were then placed in 5% silver nitrate solution, exposed to sunlight for 20 min, and rinsed with distilled water. The sections were subsequently placed in 5% sodium thiosulfate for 5 min and ten washed with distilled water. Finally, they were counterstained with nuclear fast red for 5 min. Dark brown staining indicated areas of calcification in the vessel walls. Calcification was evaluated semi-quantitatively using Image J software . The percentage of calcified area was calculated as the von Kossa–positive area normalized to the total tissue area, which was measured in 10 representative areas and expressed as a mean value.Western blot analysis was performed using anti–ROCK-2 , anti–β-catenin , anti-RUNX2 , anti–p-SAPK/JNK , anti-SAPK/JNK , anti-SMA , anti-Wnt5a , anti-Wnt3a , anti-sFRP5 , anti-sFRP4 , anti-sFRP3 , anti-sFRP2 , anti-sFRP1 , and anti-GAPDH  antibodies. Blots were immunolabeled using horseradish peroxidase-conjugated secondary antibody and incubated with chemiluminescent substrate . The Western blots were quantified using ImageJ software .2 SYBR Green Master Mix (Qiagen) and dispensed into the RT2-profiler PCR array (Qiagen). Each 96-well plate contained 84 Wnt signaling–related genes, five housekeeping genes , one genomic DNA control, three reverse transcription controls, and three PCR controls.Total RNA from rat aortic tissue was extracted using the PureLink RNA Mini Kit (Ambion). cDNA was synthesized from 0.5 μg RNA using the RT First Strand Kit . For real-time PCR, each reverse-transcription reaction product was mixed with RTn = 40), patients on hemodialysis (HD) without VC (n = 40), and patients on HD with VC (n = 40) were taken. VC was evaluated on plain x-ray of the lateral lumbar spine using a method described previously by Kauppila [To measure serum concentrations of sFRP5, blood samples from human subjects with normal renal function  according to the manufacturer’s instructions.This study was approved by the Institutional Review Board of the Gachon University Gil Medical Center . All procedures were carried out in accordance with the Declaration of Helsinki, as the study involved human participants. Written informed consent was obtained from all participants. The biospecimens and data used were provided by the Gachon University Gil Medical Center Bio Bank.t-test or Mann–Whitney U test, and comparisons among multiple groups were performed using one-way analysis of variance or the Kruskal–Wallis test followed by post hoc multiple comparison tests, as appropriate. Statistical analyses were performed using the GraphPad Prism software . p values < 0.05 were considered to indicate statistical significance.The results are presented as means ± standard error of the means. Comparisons of means between the two groups were performed using the independent Student’s