Multiporphyrinic architectures: Advances in structural design for photodynamic therapy

Rationally designed multiporphyrinic architectures for boosting photodynamic therapy (PDT) have attracted significant attentions recently years due to their great potential for light‐mediated generation of reactive oxygen species. However, there is still a gap between the structure design and their PDT performance for biomedical applications. This tutorial review provides a historical overview on (i) the basic concept of PDT for deeply understanding the porphyrin‐mediated PDT reactions, (ii) developing strategies for constructing porphyrinic architectures, like nanorings, boxes, metal‐organic frameworks (MOFs), covalent‐organic frameworks (COFs), vesicles, etc., where we classified into the following three categories: multiporphyrin arrays, porphyrinic frameworks, and others porphyrin assemblies, (iii) the various application scenarios for clinical cancer therapy and antibacterial infection. Also, the existing challenges and future perspectives on the innovation of porphyrinic architectures for clinical PDT applications are mentioned in the end section. Moreover, the porphyrinic nanomaterials with atomically precise architectures provide an ideal platform for investigating the relationship between structures and PDT outputs, design of personalized “all‐in‐one” theranostic agents, and the popularization and application in wider biomedical fields.


INTRODUCTION
Porphyrin derivates are macroheterocyclic compounds that composed of a 18 π-electron aromatic porphin unit and multiple substituted groups at the meso-position or the β-position. [3]Such molecules are extensively used as photosensitizer (PS) with two absorption bands: a strongest Soret band at ultraviolet region for a pair of degenerate electronic transitions and a Q band at visible region for another pair of degenerate transitions. [4]Recent years, it has proved that the porphyrin monomer and their constructed structures can effectively capture photons from sunlight and transfer the excited electrons or the captured energy to others substances. [2,5]Due to the intrinsic functions and the versatile structures of porphyrins, they have attracted great attentions in the fields of fluorescence, photoacoustic imaging, phototherapy, and so forth for biological research. [6,7]hotodynamic therapy (PDT), [8] due to high therapeutic effect and selectivity, noninvasive treatment, and induced antitumor immune response, has been considered as a contemporary and preferred clinical technology for the treatment of diseases.It involves the integration of photosensitizer, light source, and localized oxygen (O 2 ) in the microenvironment for generating reactive oxygen species (ROS) with high cytotoxicity to kill the pathological tissues and pathogens when triggered under light irradiation. [9]Since the first photosensitizer was reported in the 1970s and early 1980s, [10] more and more attentions were attracted to develop the new generation photosensitizers with the red-shifted maxima absorption wavelength as well as high extinction coefficients based on porphyrin macrocyclic structures, [11] which were classified into the second or the third generation photosensitizers according to their functions.Up to now, some novel porphyrin-derivated photosensitizers, such as photochlorine (Ce6), zinc-phthalocyanine, metatetrahydroxyphenylchlorin (mTHPC), etc. have been successfully developed for evaluating their PDT activity. [12]owever, it is compromised the PDT therapeutic effect of these hydrophobic porphyrins for clinical applications due to their poor circulation lifetime and undesired self-aggregation.
Accompanied by the spurring development of contemporary nanomedicines, the integration of photosensitizers into nanoparticles has been employed that can overcome most of the shortcomings of porphyrin photosensitizers for PDT activity. [13]There are numerous review articles that have highlighted the developing approaches through adsorption, encapsulation or co-precipitation of photosensitizer into the nanoparticles for PDT, such as liposomes, mesoporous silicon dioxide (SiO 2 ), polymer micelles, dendrimers and so on. [6,14,15]Such photosensitizer-containing nanoparticles can effectively increase the photosensitizer accumulation to target areas, prevent the cytotoxicity to normal tissues, and realize the precise PDT therapy.However, restricted by the low loading capacity and easy to lose, these strategies cannot be widely used for PDT.
As a generally used building block, porphyrin can be self-assembled into hierarchical structures with various well-defined morphologies, which have been extensively reported in developing light harvesting antenna for photon capture [16,17] and photocatalysis owing to the fascinating photosensitive properties of porphyrins. [18,19]In recent years, various hierarchically constructed porphyrin structures have been developed through utilizing both covalent and noncovalent approaches to synthesize different nanorings, [20] polyhedral cages, [21] frameworks, [22,23] as well as nanocapsules with well-defined structures. [24]The construction of multiporphyrinic architectures can decrease the self-aggregation and fluorescence quenching of photosensitizers, thus further improving their photophysical and photochemical properties.On the other hand, due to the unique structural feature and the improved performance of porphyrins in micro/nano structures, the hierarchically constructed porphyrinic structure presents a promising platform for antibacterial infection and/or tumor therapy (Figure 1).
In the past few decades, several excellent review articles have been addressed to the rational design of porphyrin metal-organic framework/covalent-organic frameworks (MOF/COF), [21,25,26] and porphyrinic hybrids for potential PDT applications. [14,27]Recent years, more and more research works have been reported on construction of hierarchical structures for advanced photosensitive applications.However, a comprehensive literature review that bridges the hierarchical constructed porphyrinic architecture and the PDT output is still missing up to now.Herein, the latest progress and achievements in the construction of porphyrinic structures, from multiporphyrin arrays, porphyrinic frameworks to others assemblies for PDT were emphasized in this review.Also, a summary of the representative multiporphyrinic architectures for enhancement of ROS generation and therapy of disease were listed in Table 1.Besides, it provides a straightforward overview and motivation for their application in PDT therapy of antibacterial infection and tumors.Finally, the existing challenges and future development prospects on the innovation of porphyrinic architectures for clinical PDT applications are also highlighted.

F I G U R E 1
Hierarchical construction of multiporphyrinic architectures for photodynamic therapy.

THE BASIC ASPECTS OF PDT
PDT has attracted extensive attentions for treatment of diseases since its establishment in the early 1900s. [10,52]It involves the integration of photosensitive agents, light, and accumulated molecular O 2 in situ to generate cytotoxic ROS to kill disease tissues or microbes. [53]The schematic illustrative mechanism is draw in Jablonski energy level diagram, and was shown in Figure 2.Under light irradiation, an electron of the ground state (S 0 ) is transited to the first singlet (S 1 ) excited state or the second singlet (S 2 ) excited state with high energy level, from which the excited electron can be quickly decayed to S 0 through the internal conversion (IC) to generate fluorescence or heat via a nonradiative vibration relaxation. [5][55] It is noticed that both of the I and II photodynamic progress can occur concurrently, but their proportion is dependent with the porphyrin structures, O 2 concentration and substrate presented.
The highly cytotoxic 1 O 2 produced by the PDT reaction can irreversibly damage the pathological tissue and pathogens, which is extensively used for treatment of diseases. [9]Under the guidance of a Jablonski diagram, the photophysical properties of the PS agents can largely influence their PDT efficiency for different biological application scenarios.Up to now, photosensitizers for PDT have undergo three generations through screening the chemical structures. [56]It has been proved that the rational design of multiporphyrinic architectures can greatly affect the efficiency of 1 O 2 production, which in turn facilitates their biomedical application for PDT therapy. [17]A B L E 1 A summary of representative multiporphyrinic architectures for enhanced PDT outputs.

Classification
Names Building units PDT properties Ref.

F I G U R E 2
Jablonski energy level diagram of porphyrin for photodynamic therapy (PDT).

MULTIPORPHYRIN ARRAYS
Multiporphyrin arrays are molecules that covalently or noncovalently linked by two or more porphyrin units into uniform single molecular structures.The synthetic multiporphyrin arrays can not only possess intrinsic properties of porphyrin but also afford structure-dependent biological effects like enhanced permeability and retention when used for in vivo photodynamic therapy.Besides, it has been proved that the construction of multiporphyrin arrays, to some extent, can facilitates the energy migration of excited state and hole/electron hopping of ground state, [57] which can promote their applications as photodynamic agents for antibacterial or cancer therapy.According to their constructed architectures, herein, multiporphyrin arrays were classified into porphyrinic nanorings, porphyrinic boxes, and gave an in-depth discussion in this section.

Construction of porphyrinic nanorings
Porphyrins are a group of 18 π-electron aromatic structures with symmetrical tetrapyrrole macrocycles and multiple meso-carbon bridges in their conjugated structures, [58] and are widely used for PDT due to their strong energy capture and 1 O 2 generation efficiency. Such ring-like structures have also evoked different interest in the field of single molecular electronics, and photocatalysis, especially for photodynamic photosensitizers.

Template-directed synthesis
In order to construct the uniform porphyrin nanorings, the organic ligands are employed to guide the "growth" behavior of porphyrin units via metal-ligand coordination interactions, which is defined herein as the template-directed synthesis strategy.The first example of cyclic porphyrin array was reported by Anderson and Sanders in 1990 (Figure 3A). [61]n this process, metalloporphyrin units were mediated with multipyridyl ligands to covalently linked to multiporphyrinic nanorings through the Glaser-Hay coupling reaction.Interestingly, the topological structures of nanorings showed well-relevance to the molecular structures and number of pyridyl templates.Besides, the multipyridyl templates and metal centers of porphyrin units can be further removed to construct nonmetal porphyrin cycles.

Directed synthesis
Apart from the template-mediated synthesis, another feasible strategy is direct synthesis multiporphyrin nanorings without the aid of pyridyl ligand templates.It was usually mediated by the orientation of rigid porphyrin units.In this way, the rational design of porphyrin plays an indispensable role in directing the size, shape, and structure of multiporphyrin nanorings.It was found that the porphyrin monomers were successfully coupled into square Por[4] [75] and Por[12] [76] , trianglar Por[6] [77] , hexagonal Por[12] [29] and Por[24] [30] , and so on, if changing the space orientation of reactive sites.Moreover, such developed strategy can be also used to construct more hierarchical architectures based on the cyclic porphyrin arrays.It is great essential for in depth understanding the electron transfer along the multiporphyrin nanorings for their unique photophysical properties.It has been proved that the EET process within the porphyrin arrays were adjusted by different porphyrin components, torsional mobility, linker structure, and connection motifs, [78] which were beneficial to the photodynamic reactions.Nakamura et al. synthesized three different porphyrin rings named Por [4], Por [6], and Por [8] which comprise four, six, and eight porphyrin units respectively through direct meso-meso covalent connection of porphyrin in meso−meso position. [28]As shown in Figure 3C, it was determined by the transient absorption that the excitation energy hopping rates are quite relevant to the lifetime results of 119 ± 2 fs for Por [4], 342 ± 59 fs for Por [6], and 236 ± 31 fs for Por [8], which indicated that the order of energy transfer lifetime of Por [6] > Por [8] > Por [4]  is just on the contrary with the order of dihedral angle between neighboring porphyrins.
Nowadays, numerous porphyrin nanorings with different architectures have been developed according to the multiplicity of porphyrin units and their reactivity.The same as the free porphyrin molecules, the structure of cyclic porphyrin arrays sometimes induces distortion of the porphyrin ring.It has revealed that the EET process between neighboring porphyrin units could be well-tuned by the structure of porphyrin rings [57] and the porphyrin-porphyrin linkages, [31] which would be helpful for improving the efficiency of the energy migration and the hopping of electron and hole.Therefore, with the rational design of multiporphyrinic architectures, the efficient exciton dynamics in multiporphyrinic arrays will promote the PDT reactions for 1 O 2 generation.

Construction of porphyrinic boxes
Porphyrin box is also another kind of multiporphyrinic arrays that be generally developed for artificial light harvesting and photocatalysis. [25]It is predicted such orderly arranged porphyrin arrays would facilitate the EET rates between porphyrins and enhance the PDT efficacy.Not only that, the incorporation of functional ligands with porphyrins to construct polyhedral porphyrinic cages is a useful way to endow porphyrinic construction with multifunctionalities, including shape persistency, selectivity, encapsulation, and so on.Such process is driven by controlling the orientation and interaction between porphyrin monomers and ligands, which self-organized into single-molecular porphyrin "boxes".The dimension of the inner cavities and pores of the boxes can be altered by changing the porphyrin structures and organic ligands while keeping the original topology of box structures.Importantly, such structures possess brand-new delocalized electrons and distribution, which would be meaningful to the photo capture and energy transfer in photodynamic actions.To date, various three-dimensional porphyrin or metalloporphyrin nanocages with chemically robust, welldefined structures have been developed for photochemical and biomedical applications. [21,25]Up to now, some strategies including template-directed synthesis, metal-coordinated synthesis, and direct covalent synthesis were incorporated to make the porphyrin box.

Template-directed synthesis
Template-directed synthesis is a highly effective method to well-organize the porphyrin units with geometrical or topological control of their structures.Different from the construction of porphyrin nanorings, the linkage of porphyrin units must be happened in three-dimensional space to form a "closed" cage structures.Also, the use of a space-oriented multipyridyl template could favor the cage closure step, increase the rate and yield of the desired structures.After that, the template is removed under certain condition to get a metal-free porphyrin box.What's more, this strategy can be further used to develop metal-free porphyrin boxes through the post-removing technology.
The most developed porphyrin boxes are bisporphyrin box with quadruple flexible ligands connected on each edge.In 2011, Aida and coworkers constructed a bisporphyrin Por [2] box through a bidenated endohedral metallofullerene La@C82 mediated covalent connection of tetra-alkenesubstituted metalloporphyrin (Figure 4A). [21,79]Besides, the templates of the box are able to be removed to afford an empty multiporphyrinic box.Interestingly, the cage size and cavity structure can be variable because of their four long and flexible linkers, which is important for cargo encapsulation and/or biocatalysis.
Besides, some other templates, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), [21] pyridinefunctionalized gold nanocluster, [80] have also been used to develop the multiporphyrin boxes using the same strategy.Most of the template-directed synthesis of porphyrin boxes is based on the axial coordination between the pyridine-based ligands and the metalloporphyrin units.Such binding can be also employed to develop metal-coordinated porphyrin cages.

Metal-coordinated synthesis
Metal-ligand coordination is a universal strategy to construct hierarchical architectures and is also extensively existed in natural biosystems.Porphyrin possesses rigid heterocyclic structures with excellent structural geometry and orientation of active sites.Such units can be spatially-directed by the "rigid" metal-ligand coordination because of their directivity and saturation characteristics. [81]In generally, there are two different methods to develop porphyrin polyhedral cages using metal-coordination procedure, and we denoted as "metalloporphyrin coordination strategy" and "porphyrin-metal coordination strategy" in this review.No matter which method was used, all the cage morphologies formed are predicted by the porphyrin structure and direction of coordination bond.

Metalloporphyrin coordination strategy
Metalloporphyrin coordination strategy is a way that the metal center of one porphyrin unit directly coordinated with an electron-enriched group like pyridinyl or imidazolyl of another porphyrin unit. [82]This method has been extensively explored in the past two decades.In 2002, Tsuda, Osuka et al. reported a method to quantitatively self-assemble a regular cubic porphyrin box from the dimer of para-monopyridineappended zinc(II) porphyrin, which providing a direct way for construction of metalloporphyrin boxes. [82]Based on that, Osuka, Kim et al. synthesized three different cubic porphyrin boxes B1, B2, and B3 using meso-pyridine appended zinc(II) porphyrin dimers with different length of pyridine ligands (Figure 4B). [32]Both the pump-power dependent decay and the transient absorption anisotropy decay curves indicated that the migration of excitation energy was happen between the neighboring porphyrin units in Bn boxes.It was found that the energy hopping time along the linked porphyrin units is 48 ps for B1, 98 ps for B2 and 361 ps for B3, respectively, which is well dependent with the length of ligangs.Moreover, this method can be extended for the construction of cuboid box TB2 using T-sharp mesopyridine-appended zinc(II) porphyrin trimers.It is predictable that the photophysical properties can be tuned by the conformation of porphyrin boxes, which is promising candidates for light harvesting or photodynamic therapy.
Besides, the change of N-heteroatom position and porphyrin oligomer structures were also employed to control over the architectures of metalloporphyrin boxes, such as meso-cinchomeronimide or meso-5-azaindole mediated triangular prism, [83] alkynylene-bridged bis-porphyrin regular cuboid, [84] and so on.Although great success has been made, this process can be only used to construct the metalloporphyrin boxes because of the participation of the metal center when coordination, which is also the Achilles' heel for this strategy.

Porphyrin-metal coordination strategy
Different from the metalloporphyrin coordination strategy, the porphyrin-metal coordination strategy is the one that an external metal ion or organometallic molecule is used to coordinate with the arm of a porphyrin or metalloporphyrin unit which usually terminated with N-heterocyclic group.In this process, the interaction between the porphyrin ligands and external metal species used must be thermodynamically stable to control the direction of coordination into porphyrin boxes with specific composition and uniform molecular weight.Up to now, numerous metallic species, such as Pd(II), Pt(II), Fe(II), Zn(II), Cu(I), Ir(I), Rh(I), and Ru(I), etc. have been employed to synthesize polyhedral structures.It can be predicted that the porphyrin boxes using this method can well-maintain the multi-functional cooperated properties of metal, porphyrin and cage structures.
Besides, due to the unoccupied porphyrin center when forming the structures, this method can be further used to develop multitherapeutic outputs through combination of porphyrin PDT and metal-center catalytic therapy.Tetrakis(pyridyl) porphyrin is the most used porphyrin unit, and is found that the final cage architecture can be well predicted by the pyridyl-N-atom position and the coordination bond orientation.In 2011, Nitschke and coworkers developed a new class of closed box through an efficient metal ion-ligand coordination. [33]As shown in Figure 4C, the coordination of Ni(II)-centered mesotetra(4-aminobenzyl)porphyrin (TAPP) with Fe 2+ complex (Fe(OTf) 2 ) and 2-formylpyridine in a molar ratio of 6:8:24 resulted in a closed cubic structure, from which 8 Fe 2+ ions on the vertex and 6 TAPP on the face.Besides, such method can be used to synthesize triangular prism-like structure by the coordination of three zinc(II) meso-tetra(3pyridyl)porphyrin (TPyP) panels and six Pd(en)(NO 3 ) 2 (en = ethylenediamine) building blocks. [85]Such structures could be also accessed for others cis-Pd(II) ligands, such as cis-(tmen)Pd(NO 3 ) 2 , cis-(Meen)Pd(NO 3 ) 2 , and cis-(2,2′bipy)Pd(NO 3 ) 2 . [86]n addition, cis-platinum complexes like cisplatin and oxaliplatin are Food and Drug Administration (FDA)approved molecules for cancer chemotherapy.As we known, Pt(II) ions show the similar coordination behavior with that of Pd(II) ions, it has been extensively explored for metallacage construction with different topologies.It was found that cis-Pt(PEt 3 ) 2 (OTf) 2 could coordinate with TPyP into homoleptic trigonal prism (Pt-TP1, Figure 4D), while cis-[Pt(dppf)(OTf) 2 ] can mediate the TPyP into a hexagonal prism with a diameter of 27.2 Å. [34] In the year of 2010, Stang and co-workers reported a bisporphyrin tetragonal prism through the coupling of TPyP with sodium terephthalate, and cis-(PEt 3 ) 2 Pt(OTf) 2 in a molar ratio of 2:4:8, where they respectively located in face, edge and vertex of the prism (Pt-BP1, Figure 4D). [35]Such self-assembly strategy driven by metal coordination could be employed for regulating the interporphyrin distance in bis-porphyrin tetragonal prism for a higher 1 O 2 generation by changing organic linker into a 120 • diPt(II) motif (Pt-BP2, Figure 4D). [36]Not only that, it may integrate PDT and chemotherapy functions into one structure for combined therapy with synergy.Besides, there were also a lot of polyhedral structures, such as bis-porphyrin tetragonal prism, [87] hexa-porphyrin cubes, [33] and others, has been reported by using this method.

Direct covalent synthesis
Besides, the third generally used strategy is direct covalent interconnection of porphyrin units with organic linkers, which denoted as direct covalent synthesis method here.The first porphyrin box developed using this method can be tracked back to 1977, which was developed by templatedmediated synthesis of another porphyrin units from a tetra-aldehyde-terminated porphyrin structures. [89]Recent years, dynamic covalent assembly strategy has made considerable development for various constructions because of their self-adaptability and stimuli-responsivity. [90] However, it is still extremely difficult to rational design of porphyrin boxes with a large size and high chemical stability using this method.
Porphyrin boxes with larger cavities can be well developed by the connection of building blocks based on the "Archimedean solids" stacking.Fox example, with the rational design and model stacking, six square-shaped C 4 symmetrical units and eight C 3 symmetric triangular units can be stacked into a rhombicuboctahedron-shaped box with six square faces and eight triangle faces through pointto-point connection, as shown in Figure 5A.To verified this assumption, Kim group reported a universal method to rationally design a porphyrin box (PB-1, Figure 5B) through the schiff base connection between four-connected meso-tetrakis(4-formylphenyl)porphyrin (TFPP) and triangular (2,4,6-tributoxybenzene-1,3,5-triyl)trimethanamine (TRMAB) with an inner cavity of about 1.95 nm. [37]Besides, others C 3 symmetric units with the similar terminated groups can be used to construct similar structures.The same group successfully developed a flexible porphyrin box (PB-2, Figure 5B) with the similar connection by using a triangular tris(2-aminoethyl)amine unit (TREN).
Importantly, such porphyrin boxes are very important structures with interesting chemical, photophysical, electrochemical, and biological properties, which can be further used for various applications, including catalysis, biomedical therapy, and so on. [21]It has been demonstrated that the constructed porphyrin box showed ion channel behavior for selective ion transportation across the lipid bilayer membrane. [91]Besides, the same group also developed Fe(II) porphyrin boxes using the same way to enhance active site exposure and substrate diffusion for electrochemical CO 2 -to-CO conversion. [18]If further incorporate with bipyridyl-terminated ligands, the metalloporphyrin box can be further connected to construct hierarchical superstructures using porphyrin box as building blocks. [92]

PORPHYRINIC FRAMEWORKS
Porphyrins are highly symmetrical macromolecular heterocyclic compounds with customized functional groups that can be used as building units through self-interaction or coordination with other species to form different hierarchical nanostructures.Up to now, a great number of porphyrinic framework nanostructures, including MOFs and COFs have been developed, [17,26] and have proved to be efficient scaffolds for encapsulation, light harvesting, photocatalysis, and even photodynamic therapy.Considering the framework properties and well-arranged porphyrins, the constructed porphyrinic frameworks may be potential for developing excellent PDT photosensitizers.Besides, the structures would be nanoscale dimension because the penetration/retention effect and the in vivo biodistribution are dependent to the size of nanoparticles.
In this part, we classified the porphyrinic frameworks into two sections named as porphyrinic MOFs and porphyrinic COFs, according to their constructing technology.In porphyrinic MOFs, porphyrin units are connected by metal nodes (metal ions or metal clusters) into periodical frameworks, while porphyrinic COFs for the similar frameworks but being bonded covalently with other organic components.In addition, we totally classified as others porphyrinic assemblies for others constructed well-organized structures through self-assembly methods.The component and structure of porphyrinic MOFs are great essential for photosensitivity.Thus, much attentions should be focused to constructing porphyrinic architectures to meet the demand for PDT therapy in biological fields.

MOF synthesis
Although it is formed based on metal-ligand bond formation, MOF is a crystalline framework that is outward extended according to specific crystal structure, which is quite different from the metal coordination synthesized porphyrin It has been showed that the topology of porphyrinic MOFs, including porphyrin number per node, pore size, porphyrin distance, and so forth play important roles for 1 O 2 generation for photodynamic therapy. [95]In 1991, since Robson group reported the first porphyrin MOF example with Pd(II) TPyP and Cd 2+ ions as nodes, [96] various kind of porphyrinic MOFs from the structural construction to advanced applications have been extensively developed and explored.Considering the synthesis procedures and application fields, the design of porphyrin structures and metal nodes are essential for regulating the hyperfine structures of porphyrinic MOFs.The most used porphyrin units for construction of MOFs were listed out in Figure 6.The carboxy-or pyridylterminated porphyrin units are the generally used units for MOF formation, because they can bond with metal nodes in a well-organized manner.Up to now, carboxy-based H 4 TCPP and its metalized derivates have been extensively used to develop porphyrinic MOF structures. [23,97]The cooperation of H 4 TCPP with metal ions (Mn(II), Fe(II), Co(II), Ni(II), Cu(II)) or metal clusters (Zr-or Hf-) resulted in the formation of MOFs with typical topologies by a solvothermal method.For example, MIL-141 with FeCl 3 •n(H 2 O) coordination, [98] PMOF-3 with [Fe(OH)O 4 ] n 6+ , [99] Hf-PCN-222 with Hf 6 O 4 OH 4 (COO) 8 (OH) 4 (H 2 O) 4 , [100] Al-PMOF with Al(OH)O 4 , [19] and so on.Apart from that, Zr 6 clusters were also widely used for MOF synthesis because of their high connectivity and high charge density.H 4 TCPP or H 4 TCPP(M) (M = Fe, Co, Ni, Cu, Zn) were coordinated with Zr 6 clusters to build several porphyrinic MOFs denoted as PCN-138, [101] PCN-222 and MOF-545, [102] PCN-223, [22] NU-902, [103] PCN-224, [104] PCN-225, [105] PCN-226, [106] and so on.
Just as the porphyrin derivatives, the constructed porphyrinic MOFs were also extensively explored for cancer therapy and antibacterial PDT through the down-regulation of MOF structures to nanosized level.Also, the kind of metal and porphyrin unit, the coordination reaction, and even reaction time etc. can affect the size and structure of MOF crystals.Because of the existence of porphyrin units, such structures were used for antibacterial or antitumor PDT.Besides, with combining the properties of cavity encapsulation, metallacatalysis, and fluorescence, such porphyrinic MOFs also offer a variety of attractive features for PDT combined multimodal therapy.

PDT activity of porphyrinic MOFs
The formation of MOF structures can efficiently inhibit the unpredicted π-π stacking of the porphyrin motifs and thus enhance the ISC from S1 state to the T1 state, which increase the efficiency of PDT.Wang et al. reported a new method to construct 2D mono-layered Zr-Por MOF nanosheets (UNs-FA, Figure 7A). [38]The UNs-FA MOF nanosheets exhibited outstanding photocatalytic activity because of their intriguing aesthetic architectures and unique properties.Besides, it has been proved the incorporation of heavy atoms into PDT agents can improve the intersystem crossing process for the "heavy atom" effect.Lin et al. reported a nanoscale Hf-porphyrin MOF nanosheet in 2014 by the solvothermal reaction between HfCl 4 and H 2 -BCPP for photodynamic therapy of neck cancer. [39]The porphyrinic MOF could efficiently generates 1 O 2 , and greatly enhanced photodynamic antitumor therapy efficacy.Besides, some metal ions like Cu(II) in the porphyrin center will capture the excited electrons and promote charge transfer and ROS generation. [40,107]The fluorescence sensor results indicated that Cu(II) porphyrin-based MOFs generated about double amount of ROS than that of porphyrin-based MOFs under light irradiation, which suggested that Cu(II) in MOFs could boost ROS generation.
In order to continue improving the PDT efficacy of MOFs, MOF particle size and active target have been considered to facilitate efficient PDT for the enhancement of permeability and retention.Zhou et al. developed a new method to synthesize a series of nanoscale porphyrinic MOFs PCN-224 with size distribution around 30, 60, 90, 140, and 190 nm (Figure 7B). [41]Interestingly, it was found that the PCN-224 MOFs showed a significant size-relevant behavior on cellular uptake and PDT activity, and PCN-224 with size about 90 nm had a preferential uptake behavior and remarkable antitumor PDT efficacy over other sizes.
Besides, most of metal centers afford "nanoenzyme" properties, which can be used to catalyze the production of toxic species.Such constructed porphyrin MOFs afford the combined chemodynamic and photodynamic effect. [42]eanwhile, when irradiated under light exposure, the excited electron of porphyrinic MOFs can return to S 0 state via non-radiative vibration relaxation for photothermal therapy (PTT).In a recent study, researchers made a Cu-PCN-224 MOF for combined PDT and PTT.It was found that the doped Cu(II) ions in Cu-PCN-224 MOF could suppress the recombination of electron and hole pair and thus accelerate the electron transfer with the enhanced 1 O 2 yields.Furthermore, the Cu-PCN-224 MOF could also enhance the photothermal conversion due to the low-lying d-d states (Figure 7C). [43,108]n addition, Lin et al. reported a nanoscale Cu-MOF with Cu(II)-mediated coordination of porphyrin for radical therapy, in which Cu(II) can be employed for estradiol-induced chemodynamic therapy and PDT in vivo. [109]Pei et al. reported a MOF nanorice (Fe-MOF/Fe 2 O 3 ) with Fe as metal nodes, which can not only catalyze the production of •OH via Fenton reaction and overcome the hypoxic environment of tumor tissue by in situ generation of oxygen but also can promote energy transfer between porphyrin and oxygen molecules for PDT treatment. [110]

Porphyrinic COFs
Similar with the porphyrinic MOFs, porphyrinic COFs are a family of organic porous crystalline skeletons with superfine integration of porphyrin units and organic linkers via covalent or dynamic covalent interactions. [26,111]In 2005, Yaghi and co-workers successfully synthesized the first COF framework by using the topological design principle, different porphyrinic COF structures with atomic precision have been progressed significantly from two-dimensional (2D) sheets to three-dimensional (3D) bulks.Such porphyrinic frameworks have not only shown great advantages for separation, gas adsorption/desorption, biocatalysis, light harvesting, and photophysical and photochemical applications, but also showed great potential in PDT applications.As shown in Figure 8A, different porphyrin units and organic linkers were developed to construct porphyrinic COFs with various topologies and functions.For getting better results, scientists always paid great attentions in the following aspects to improve the PDT efficacy: (1) the spatial scalable topological structures, (2) the diversified covalent bonding, and (3) overcoming the photodynamic obstacles and combined multimodal therapy.The optimization of spatial scalable topological structures is the primary way to improve the PDT efficacy.Hemotetrasubstituted porphyrin is a square C 4 symmetric monomer, it can be usually connected by a linear C 2 -symmetric linker to a 2D COF with sql-topology through [4 + 2] condensation (Figure 8B).Jiang and co-workers prepared the boronicester-linked porphyrin COF via condensation of TBPP(M) with 1,2,4,5-tetrahydroxybenzene (15, THB). [112]In addition, such sql-topological 2D porphyrin COF could be also constructed via [4 + 4] condensation reaction of a square C 4 porphyrin and a quadrilateral linker. [113]Besides, some other topological COF could be achieved by adjusting the geometry of the organic linkers and porphyrin geometry.Wang and co-workers constructed a 3D porphyrinic COF from square porphyrin and tetrahedral linkers connected by [4 + 4] imine condensation reactions, which showed a interpenetrated pts-topology (Figure 8D). [45]alik et al. reported that the [2 + 3] condensation of a C 2 -symmetric TBPP with a C 3 -symmetric trigonal knot HHTP ( 16) led to a 2D hcb-topological COF, which features hexagonal cavities with a pore size about 4.6 nm (Figure 8C). [114]Besides, the intra-couple reaction of porphyrins also provide an optimal geometry for COF synthesis.For example, the triazine cyclization reaction of bis(cyanophenyl)porphyrin, [115] self-polycondensation reaction of C 2 -symmetric A 2 B 2 -Por, [116] and so on.It was indicated that such highly-conjugated frameworks can behavior as a "green path" for electron transfer and substance migration, which promoting the research for various applications, especially for heterogeneous catalysis and PDT.
Researchers also developed diversified covalent bonding methods of COFs to meet different application scenarios.Up to now, some coupling reactions, such as Suzuki coupling, [117] Sonogashira-Hagihara coupling, shiff base bond, [118] boronic esterification, triazine, and so on have also been employed for successful COF synthesis.Depending on the topological structures of porphyrins and organic linkers, the porphyrinic COFs were divided into 2D or 3D structures.In order to solving the metabolism problem, porphyrinic COF crystalline construction by the reversible covalent interactions is being a developing tendency because of their dynamic responsive abilities.
To date, three reversible covalent reactions, named boronate ester reaction, trimerization of nitriles, and schiff base reaction, have been extensively explored to produce "smart" porphyrinic COFs.Among them, the schiff base linkage is the most used connection manner in 2D or 3D COF crystalline construction for PDT application because of their pH-triggered degradation. For example, Wang and co-workers developed pts-topological porphyrinic COF from coordination of TFPP and tetra(paminophenyl)methane (14, TAPM), which can behavior as heterogeneous catalyst for improved 1 O 2 generation under photoirradiation (Figure 8D). [45]Chen et al. developed porphyrinic COF structures (COF-366 NPs) from TAPP and terephthaldehyde (1) for reaching combination of PDT and PTT in vivo (Figure 9A). [46]If introducing active sites into the COF skeletons, the developed COF materials can be further functionalized for advanced applications.
Because of the oxygen-consuming process, the efficiency of photodynamic therapy is always restricted in the lowoxygen region.In order to overcome the hypoxia obstacles in tumor cells, oxygen-carried COFs have been developed for improving the production of 1 O 2 in deep tumor surrounding.Recently, perfluorocarbon have been demonstrated their good biosafety and high oxygen carrying capacity, which might be extremely meaningful to deliver oxygen for alleviating tumor hypoxia and enhancing PDT. [121] carry molecular oxygen for improving the tumor oxygenation efficiently (Figure 9B). [47]Importantly, it was proved that such COFs can load oxygen during the blood circulation period and controllably release O 2 in tumor regions for alleviating tumor hypoxia and enhancing PDT in vivo.
Furthermore, porphyrinic COF is a promising platform for combining photodynamic therapy with others therapeutic models.Different functional blocks are combined with COFs through encapsulation, absorption or modification to develop multimodal synergistic therapeutic strategies.Besides, some others strategies were used, like co-encapsulation of GOx and CAT for long-term starvation therapy and enhanced photodynamic therapy, [48] functionalization with PD-L1 gene silencing gene for combined photodynamic therapy and genetic immunotherapy, [122] and so on, for improving the therapeutic outcome.

OTHERS PORPHYRINIC ASSEMBLIES
Apart from the multiporphyrin nanoarrays and porphyrinic frameworks, some others porphyrinic assemblies, including but not limited to amphiphilic micelles, [50] vesicles, [123] monolayered capsules, [124] have been widely used for high efficient PDT therapy.For example, Bai and Fan et al. report a porphyrin nanoparticle through porphyrin assembly, which can be further surrounded by amorphous silica layer through silicate sol-gel process to make core-shell porphyrinic structures. [125]The core-shell structured particles can be well accumulated in the tumor cells by the facilitation of FA ligands.Interestingly, it was found to have a highyield generation of 1 O 2 for enhanced PDT activity.Zhang et al. developed a supramolecular porphyrin micelle through host-guest interaction for photodynamically combating bacterial infections and biofilm dispersion. [126]Wang et al. reported amphiphilic porphyrin photosensitizers terminated with triphenylphosphine units, which could self-assembly into amphiphilic micelles with enhanced permeability and retention.The nanoparticles also show high 1 O 2 yields for photodynamic therapy (Figure 10A). [50]esides, Shi and co-workers reported a self-assembly strategy for producing biomimetic (Gd/Zn) porphyrin nanostructures with enhanced photodynamic therapy. [127]Lai reported a robust and uniform porphysome through amphiphilic self-assembly strategy, which indicated to be an efficient PDT agents for theranostic applications. [123]Liu et al. reported a porphyrin polymer nanocapsule for development of biomimetic cascade nanoreactor, which showed combined therapeutic efficiency of starvation and photodynamic therapy (Figure 10B). [24,51]Therefore, it has been concluded that the rational design of porphyrinic structures plays a vital role in improving the photodynamic properties, as well as realizing multimodal combined therapeutic strategies.

6
CLINICAL APPLICATIONS

Cancer therapy
Photodynamic cancer therapy has been recognized as an attractive innovation for treatment of cancers.Up to now, various porphyrinic nanomaterials with hierarchically constructed structures have been extensively used for cancer therapy.These porphyrinic structures can improve the production of cytotoxic 1 O 2 by limiting the aggregation porphyrin sensitizers.On the other hand, multiporphyrinic architectures with rational size can enhance the penetration and retention effect in tumor sites, thus improving the photodynamic cancer therapeutic efficiency.However, the hypoxic tumor microenvironment will weaken the production ability of cyto-toxic 1 O 2 because of the O 2 -dependent process.In order to deal with the hypoxia obstacles in tumor cells, various kind of additive functions were designed to enhance the oxygen concentration and porphyrinic nanoparticle accumulation, or decrease the reductive glutathione in hypoxic tumor cells.For example, incorporation of oxygen carrier for targeted delivery, in situ decomposition of H 2 O 2 using enzyme and catalyst, biomimetic photosynthesis of oxygen, inhibition of cell respiration, and surface modification with an active targeting ability. [55,128]he therapeutic efficiency of PDT is inhibited by the hypoxia microenvironment of tumor tissues.To reverse this issue, Xiao et al. reported a novel oxygen evolving MOF complex through coating with a thin MnO 2 layer and cancer cell membrane for hypoxia reversion and active target (Figure 11A). [129]The decomposition of MnO MOF nanoplatform to regulate tumor hypoxia and reducibility simultaneously in order to enhanced PDT. [130]Yuan and co-workers constructed a glutathione-responsive nitric oxide (NO) producing porphyrinic MOF nanosystem for enhanced photodynamic therapy by enhancing ROS production through glutathione (GSH) depletion and hypoxia alleviation. [131]esides, porphyrinic frameworks were usually used for encapsulation of chemotherapeutics, photothermal agents, enzymes for synergistic therapies through in situ encapsulation or post-functionalization strategies because of their porous frameworks. [44,132]Some active targeting strategies, like biomolecule modification, membrane camouflage, and so forth were also effective strategies for improving the recognition with cancer membrane. [41,133]s we know, cis-platinum derivates are quite important metal complexes and widely used for cancer chemotherapy.With the two-in-one combination of platinum and porphyrin, such systems are ideal candidates for combination of chemoand photodynamic therapy.Inspired by this, Stang and coworkers used the above Pt-BP2 box for PDT therapy of cancer cells in 2020. [36]It was found that the Pt-BP2 box structures can efficiently prevents the unpredicted stacking of the porphyrin units, which results in a higher 1 O 2 production for PDT.Besides, the tumor growth inhibition ratio of its nanoparticle group for 4T1 cancer cells-bearing mice was 98.4%, while those for only Pt-BP2, diplatinium(II) motif, porphyrin nanoparticle upon light irradiation, and cisplatin were measured to be only 51.5%, 37.3%, 60.5%, and 31.2%,respectively.
In 2017, Chen et al. discreted the Pt-BP1 cage as a multimodal therapeutic scaffolds for combined chemoand photodynamic therapy (Figure 11B). [134]The targeted metallacage-loaded nanoparticles (MNPs) were prepared through co-precipitation of Pt-BP1 cage and active target for improved blood circulation and active targeting ability.It is indicated that the fluorescent emission and photodynamic efficacy for singlet oxygen production was dramatically improved, which were benefiticial for bioimaging and PDT therapy.Clearly, the tumor volume of the experiment group (MNPs+L) exhibited nearly 100% inhibition for the mice bearing U87MG tumors compared with the phosphate buffer solution (PBS) group, while only 6.15% for light, 32.0% for cisplatin, 48.3% for cPt, 70.3% for MNPs, and 86.2% for TPPNPs+L, respectively.Besides, it also showed the same tendency from the tumor weight evaluation and survival percent results.

Antibacterial infection
Photodynamic therapy has been demonstrated an ideal noninvasive theranostic approaches for anti-bacterial infections, even for multi-resistant bacterial infections. [108,135,136]The produced high cytotoxic 1 O 2 from PDT can effectively inhibit the growth of bacteria in vitro and in vivo, which can be used for antibacterial and anti-infection therapy.Researchers usually make an in-depth exploration to improve the photodynamic antibacterial therapy in the following aspects: (1) rational design of novel porphyrinic architectures with improved production ability of cytotoxic 1 O 2 under light irradiation, (2) improving the specific accumulation of porphyrinic nanomaterials in pathogenic bacteria, (3) selective photodynamic antibacterial therapy while friendly to physiological tissues.Besides, in order to kill the bacteria actively, numerous species including but not limited to antibotics, metal ions, nanoparticles, enzymes, solid peroxides, and so forth have been employed into the porphyrinic architectures to improve the synergistic therapeutic efficiency.For example, Yao et al. reported a light-activated biodegradable COF-integrated heterojunction for combined photodynamic, photothermal and gaseous therapy of chronic wound infection (Figure 12A). [49]They constructed monolayered 2D porphyrin-based COF nanosheets (TP-Por CON) for synergizing photodynamic and photothermal therapy under red light irradiation (635 nm).After encapsulating nitric oxide donor BNN6, the TP-Por CON@BNN6 nanosheets exhibited excellent mice wound healing ability in vivo, meanwhile afford favorable biocompatibility and biodegradability, low phototoxicity and anti-inflammatory properties.Jiang et al. reported a boronic acid-decorated porphyrinic Zr-MOF and found it possess 10−20 times PDT antibacterial efficiency higher than those without the targeting ligand (Figure 12B). [107]Importantly, such porphyrinic architectures can be used to create clinically used band-aids for sensing and treatment of bacterial infection. [137]

CONCLUSION AND OUTLOOK
Porphyrins and their derivatives have demonstrated their great talent for used as photosensitizers for photodynamic therapy.As unique symmetrical planar units, they can be well-organized for hierarchical construction of micro/nano porphyrinic structures, such as multiporphyrin arrays, frameworks, and others assemblies.It has indicated that the development of porphyrinic structures can not only overcome the drawbacks of porphyrin molecules under physiological conditions, but also the integration of constructed structures and porphyrin functions that improving the EET rates for improving PDT efficiency, enhancing penetration and retention (EPR), and even development of "all-in-one" theranostic nanoagents.In the review article, the recent progress in hierarchical construction of porphyrinic structures and their appliance for cancer therapy and antibacterial therapy were emphasized.
According to the previously reported work, we have concluded that the rational design of multiporphyrinic architectures was great essential to improve their photophysical properties and PDT performance.All the porphyrin blocks, linkage types, arranged behavior and distance, and so forth can affect the final EET rates and the photoinduced 1 O 2 production.Not only that, in order to further improving the therapeutic outputs for cancers and bacterial infections, various kind of agents are incorporated to construct different porphyrinic architectures through coordination, covalent linking, co-assembly, and so forth for combination of PDT with other therapy modalities, including chemo-, chemodynamic, photothermal, and immune-therapies to reach the maximum outputs.
However, there are still some concerns and challenges related to porphyrinic architectures, and enhancement of their PDT performance for clinical applications that deserve further consideration.First, despite a great number of impressive progress reported on porphyrinic architectures for PDT, in-depth understanding of structure-activity relationship is still in its infancy and confronts many challenges.Second, the design and development of smart "all-in-one" theranostic platforms using porphyrinic architectures should be strengthened.Porphyrin is a multifunctional building blocks, more efforts should be focused to achieve multimodal synergistic therapy through combination with diagnosis methods.Third, developing the customizable porphyrinic architectures to meet the requirements of personalized photodynamic therapy.Such materials should be deeply and widely explored to meet the clinical requirements in broader application scenarios.Fourth, porphyrinic architectures with deeper PDT therapy should be highlighted for clinical applications since the limited penetration of light for clinical use.Therefore, the hierarchically constructed porphyrinic architectures have showed great talent for PDT of cancers and bacterial infections, and more progress in porphyrinic architectures will be achieved in future.

A U T H O R C O N T R I B U T I O N S
Y. G., Y. L., and Z. X. contributed equally to this work, and all authors have read and approved the final manuscript.

A C K N O W L E D G M E N T S
This work was financially supported by the National Key R&D Program of China (grant number: 2020YFA0908500), the National Natural Science Foundation of China (grant numbers: 22371062, 22001054, 22075065, and 22275046), the Zhejiang Provincial Natural Science Foundation (grant number: LY23E030001), and the Hangzhou Leading Innovation and Entrepreneurship Team Project (grant number: TD2022001).

C O N F L I C T O F I N T E R E S T S TAT E M E N T
The authors declare no conflict of interest.

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I G U R E 5 (A) Schematic illustration for the design of the covalent porphyrin box (PB).(B) Synthetic scheme and crystal structures of porphyrin boxes (PB-1 and PB-2).Adapted with permission from ref 37 Copyright 2015 Wiley-VCH.

F I G U R E 6
Representative molecular structures of porphyrin-based linkers for the synthesis of 2D and 3D metal-organic frameworks (MOFs).Reproduced with permission from refs.97, 39 Copyright 2022 and 2014 American Chemical Society, respectively.
Liu et al. reported a novel fluorinated COF nanomaterials by utilizing one-pot esterification of perfluorosebacic acid (17) and THPP.Such fluorinated COF can upload perfluoro-15-crown-5-ether to F I G U R E 8 Representative building blocks that have been utilized for the construction of porphyrinic covalent-organic frameworks (COFs) with different topologies.Reproduced with permission from refs 112, 114, 45 Copyright 2012 Wiley-VCH, 2014 and 2017 American Chemical Society, respectively.

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I G U R E 9 (A) The synthesis of covalent-organic framework (COF)-366 NPs for combined photodynamic therapy (PDT) and photothermal therapy (PTT) cancer therapy.(B) A scheme illustrating the synthesis route of O2-preloaded PFCE@THPPpf-PEG.Reproduced with permission from refs.46, 47 Copyright 2019 Elsevier and 2018 Wiley-VCH, respectively.
2 under acidic tumor microenvironment can produce oxygen bubble to improve the O 2 -involved photodynamic reaction in situ.Meanwhile, the decomposed Mn(II) ions can be used to catalyze the Fenton reaction for chemodynamic therapy (CDT).In addition, Zhang et al. developed a MnFe 2 O 4 @ F I G U R E 1 0 Schematic presentation of (A) an acid-triggered supramolecular porphyrinic micelles and (B) porphyrinic capsule encapsulated with GOx and CAT with antibacterial photodynamic therapy (PDT) activity.Reproduced with permission from refs.50, 51 Copyright 2021 Wiley-VCH and 2021 MDPI, respectively.F I G U R E 1 1 (A) Synergic mechanism of constructed Cu-PCN-224 for photodynamic therapy (PDT) and photothermal therapy (PTT).(B) Schematic illustration of MNPs accumulation in tumor tissue by EPR effect for cancer therapy.Reproduced with permission from ref. 129, 134 Copyright 2019 American Chemical Society and 2018 Nature Publishing Group, respectively.

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I G U R E 1 2 (A) Schematic representation of the TP-Por CON@BNN6 for antibacterial and anti-infection therapy.(B) Schematic illustration of the multivariate photosensitive metal-organic frameworks (MOFs) with synergistic bacterial-binding functions for efficient healing of a chronic wound infected with MDR bacteria.Reproduced with permission from refs.49, 107 Copyright 2021, 2022 American Chemical Society, respectively.