Supramolecular coordination platinum metallacycle-based multilevel wound dressing for bacteria sensing and wound healing.

The exploitation of novel wound healing methods with real-time infection sensing and high spatiotemporal precision is highly important for human health. Pt-based metal-organic cycles/cages (MOCs) have been employed as multifunctional antibacterial agents due to their superior Pt-related therapeutic efficiency, various functional subunits and specific geometries. However, how to rationally apply these nanoscale MOCs on the macroscale with controllable therapeutic output is still challenging. Here, a centimeter-scale Pt MOC film was constructed via multistage assembly and subsequently coated on a N,N'-dimethylated dipyridinium thiazolo[5,4-d]thiazole (MPT)-stained silk fabric to form a smart wound dressing for bacterial sensing and wound healing. The MPT on silk fabric could be used to monitor wound infection in real-time through the bacteria-mediated reduction of MPT to its radical form via a color change. The MPT radical also exhibited an excellent photothermal effect under 660 nm light irradiation, which could not only be applied for photothermal therapy but also induce the disassembly of the Pt MOC film suprastructure. The highly ordered Pt MOC film suprastructure exhibited high biosafety, while it also showed improved antibacterial efficiency after thermally induced disassembly. In vitro and in vivo studies revealed that the combination of the Pt MOC film and MPT-stained silk can provide real-time information on wound infection for timely treatment through noninvasive techniques. This study paves the way for bacterial sensing and wound healing with centimeter-scale metal-organic materials.

Metallacage-based enhanced PDT strategy for bacterial elimination via inhibiting endogenous NO production.

Antibiotics are among the most used weapons in fighting microbial infections and have greatly improved the quality of human life. However, bacteria can eventually evolve to exhibit antibiotic resistance to almost all prescribed antibiotic drugs. Photodynamic therapy (PDT) develops little antibiotic resistance and has become a promising strategy in fighting bacterial infection. To augment the killing effect of PDT, the conventional strategy is introducing excess ROS in various ways, such as applying high light doses, high photosensitizer concentrations, and exogenous oxygen. In this study, we report a metallacage-based PDT strategy that minimizes the use of ROS by jointly using gallium-metal organic framework rods to inhibit the production of bacterial endogenous NO, amplify ROS stress, and enhance the killing effect. The augmented bactericidal effect was demonstrated both in vitro and in vivo. This proposed enhanced PDT strategy will provide a new option for bacterial ablation.

Supramolecular Coordination Complexes for Synergistic Cancer Therapy.

Supramolecular coordination complexes (SCCs) are predictable and size-tunable supramolecular self-assemblies constructed through directional coordination bonds between readily available organic ligands and metallic receptors. Based on planar and 3D structures, SCCs can be mainly divided into two categories: metallacycles (e.g., rhomboidal, triangular, rectangular, and hexagonal) and metallacages (e.g., tetrahedral, hexahedral, and dodecahedral). The directional coordination bonds enable the efficient formation of metallacycles and metallacages with well-defined architectures and geometries. SCCs exhibit several advantages, including good directionality, strong interaction force, tunable modularity, and good solution processability, making them highly attractive for biomedical applications, especially in cellular imaging and cancer therapy. Compared with their molecular precursors, SCCs demonstrate enhanced cellular uptake and a strengthened tumor accumulation effect, owing to their inherently charged structures. These properties and the chemotherapeutic potential inherent to organic platinum complexes have promoted their widespread application in antitumor therapy. Furthermore, the defined structures of SCCs, achieved via the design modification of assembly elements and introduction of different functional groups, enable them to combat malignant tumors through multipronged treatment modalities. Because the development of cancer-treatment methodologies integrated in clinics has evolved from single-modality chemotherapy to synergistic multimodal therapy, the development of functional SCCs for synergistic cancer therapy is crucial. While some pioneering reviews have explored the bioapplications of SCCs, often categorized by a specific function or focusing on the specific metal or ligand types, a comprehensive exploration of their synergistic multifunctionality is a critical gap in the current literature.In this Account, we focus on platinum-based SCCs and their applications in cancer therapy. While other metals, such as Pd-, Rh-, Ru-, and Ir-based SCCs, have been explored for cancer therapy by Therrien and Casini et al., platinum-based SCCs have garnered significant interest, owing to their unique advantages in antitumor therapy. These platinum-based SCCs, which enhance antitumor efficacy, are considered prominent candidates for cancer therapies owing to their desirable properties, such as potent antitumor activity, exceptionally low systemic toxicity, active tumor-targeting ability, and enhanced cellular uptake. Furthermore, diverse diagnostic and therapeutic modalities (e.g., chemotherapy, photothermal therapy, and photodynamic therapy) can be integrated into a single platform based on platinum-based SCCs for cancer therapy. Consequently, herein, we summarize our recent research on platinum-based SCCs for synergistic cancer therapy with particular emphasis on the cooperative interplay between different therapeutic methods. In the Conclusions section, we present the key advancements achieved on the basis of our research findings and propose future directions that may significantly impact the field.

Metal-organic cycle-based multistage assemblies.

It is well known that chemical compositions and structural arrangements of materials have a great influence on their resultant properties. Diverse functional materials have been constructed by using either biomolecules (peptides, DNA, and RNA) in nature or artificially synthesized molecules (polymers and pillararenes). The relationships between traditional building blocks (such as peptides) have been widely investigated, for example how hydrogen bonds work in the peptide multistage assembly process. However, in contrast to traditional covalent bond-based building blocks-based assembly, suprastructures formed by noncovalent bonds are more influenced by specific bond features, but to date only a few results have been reported based on noncovalent bond-based building block multistage assembly. Here, three metal­organic cycles (MOCs) were used to show how coordination bonds influence the bimetallacycle conformation then lead to the topology differences of MOC multilevel ordered materials. It was found that the coordination linker (isophthalate-Pt-pyridine) is an important factor to tune the shape and size of the MOC-derived suprastructures.

Phenylthiol-BODIPY-based supramolecular metallacycles for synergistic tumor chemo-photodynamic therapy.

The development of more effective tumor therapy remains challenging and has received widespread attention. In the past decade, there has been growing interest in synergistic tumor therapy based on supramolecular coordination complexes. Herein, we describe two triangular metallacycles (1 and 2) constructed by the formation of pyridyl boron dipyrromethene (BODIPY)-platinum coordination. Metallacycle 2 had considerable tumor penetration, as evidenced by the phenylthiol-BODIPY ligand imparting red fluorescent emission at ∼660 nm, enabling bioimaging, and transport visualization within the tumor. Based on the therapeutic efficacy of the platinum(II) acceptor and high singlet oxygen (1O2) generation ability of BODIPY, 2 was successfully incorporated into nanoparticles and applied in chemo-photodynamic tumor therapy against malignant human glioma U87 cells, showing excellent synergistic therapeutic efficacy. A half-maximal inhibitory concentration of 0.35 µM was measured for 2 against U87 cancer cells in vitro. In vivo experiments indicated that 2 displayed precise tumor targeting ability and good biocompatibility, along with strong antitumor effects. This work provides a promising approach for treating solid tumors by synergistic chemo-photodynamic therapy of supramolecular coordination complexes.

Long wavelength-emissive Ru(II) metallacycle-based photosensitizer assisting in vivo bacterial diagnosis and antibacterial treatment.

Ruthenium (Ru) complexes are developed as latent emissive photosensitizers for cancer and pathogen photodiagnosis and therapy. Nevertheless, most existing Ru complexes are limited as photosensitizers in terms of short excitation and emission wavelengths. Herein, we present an emissive Ru(II) metallacycle (herein referred to as 1) that is excited by 808-nm laser and emits at a wavelength of ∼1,000 nm via coordination-driven self-assembly. Metallacycle 1 exhibits good optical penetration (∼7 mm) and satisfactory reactive oxygen species production properties. Furthermore, 1 shows broad-spectrum antibacterial activity (including against drug-resistant Escherichia coli) as well as low cytotoxicity to normal mammalian cells. In vivo studies reveal that 1 is employed in precise, second near-infrared biomedical window fluorescent imaging-guided, photo-triggered treatments in Staphylococcus aureus-infected mice models, with negligible side effects. This work thus broads the applications of supramolecular photosensitizers through the strategy of lengthening their wavelengths.

Self-assembled Pt(II) metallacycles enable precise cancer combination chemotherapy.

Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a disparate mechanism of action, in precise arrangements for combination chemotherapy. Formulation of the drug-loaded metallacycles with folic acid­functionalized amphiphilic diblock copolymers furnished nanoparticles with good solubility and stability in physiological conditions. Folic acids on the surface of the nanoparticles promote their internalization into cancer cells. The intracellular reductive environment of cancer cells induces the release of the drug molecules at an exact 1:1 ratio, leading to a synergistic anticancer efficacy. In vivo studies on tumor-bearing mice demonstrated the favorable therapeutic outcome and minimal side effects of the combination chemotherapy approach based on a self-assembled metallacycle.

Anthracene-induced formation of highly twisted metallacycle and its crystal structure and tunable assembly behaviors.

Polycyclic aromatic hydrocarbons (PAHs) continue to attract increasing interest with respect to their applications as luminescent materials. The ordered structure of the metal-organic complex facilitates the selective integration of PAHs that can be tuned to function cooperatively. Here, a unique highly twisted anthracene-based organoplatinum metallacycle was prepared via coordination-driven self-assembly. Single-crystal X-ray diffraction analysis revealed that the metallacycle was twisted through the cooperation of strong π···π stacking interactions and steric hindrance between two anthracene-based ligands. Notably, the intramolecular twist and aggregation behavior introduced restrictions to the conformational change of anthracenes, which resulted in increased emission intensity of the metallacycle in solution. The emission behaviors and suprastructures based on the highly twisted metallacycle can be modulated by the introduction of different solvents. This study demonstrates that this metallacycle with highly twisted structure is a promising candidate for sensing and bioimaging applications.

A NIR-Light-Activated and Lysosomal-Targeted Pt (II) Metallacycle for Highly Potent Evoking of Immunogenic Cell Death that Potentiates Cancer Immunotherapy of Deep-Seated Tumors.

Though platinum (Pt)-based complexes have been recently exploited as immunogenic cell death (ICD) inducers for activating immunotherapy, the effective activation of sufficient immune responses with minimal side effects in deep-seated tumors remains a formidable challenge. Herein, we propose the first example of a near-infrared (NIR) light-activated and lysosomal targeted Pt(II) metallacycle (1) as a supramolecular ICD inducer. 1 synergistically potentiates immunomodulatory response in deep-seated tumors via multiple-regulated approaches, involving NIR light excitation, boosted reactive oxygen species (ROS) generation, good selectivity between normal and tumor cells, and enhanced tumor penetration/retention capabilities. Specifically, 1 has excellent depth-activated ROS production (~ 7 mm), accompanied by strong anti-diffusion and anti-ROS quenching ability. In vitro experiments demonstrate that 1 exhibits significant cellular uptake and ROS generation in tumor cells as well as respective multicellular tumor spheroids. Based on these advantages, 1 induces a more efficient ICD in an ultralow dose (i.e., 5 µM) compared with the clinical ICD inducer-oxaliplatin (300 µM). In vivo, vaccination experiments further demonstrate that 1 serves as a potent ICD inducer through eliciting CD8+/CD4+ T cell response and Foxp3+ T cell depletion with negligible adverse effects. This study pioneers a promising avenue for safe and effective metal-based ICD agents in immunotherapy.

Platinum(II)-Metallaclip-Based Theranostics for Cell Imaging and Synergetic Chemotherapy-Photodynamic Therapy.

Supramolecular coordination complexes formed by coordination-induced assembly not only avoid the loss of activity of precursors but also provide an efficient way for controlled release, which can be further used in various fields of biology such as drug delivery, cell imaging, and tumor treatment. In this work, a PtII metallaclip (4) was prepared from 4-[4-(1,2,2-triphenylvinyl)phenyl]pyridine (1), 5,10,15-triphenyl-20-(pyridin-4-yl)porphyrin (2), 90o Pt, and glycol-chain-modified isophthalic acid (3) in an acetone/water mixture through the "coordination-driven self-assembly" method. 31P and 1H NMR spectroscopy and high-resolution mass spectrometry were used to characterize the obtained metallaclip 4. 4 can self-assemble into fluorescent nanostructures in aqueous solution because of the tetraphenylethylene unit and its amphiphilic nature. Importantly, the fluorescent nanoparticles not only can be employed for cell imaging but also can generate singlet oxygen (1O2) under 660 nm laser irradiation and the release of Pt drug in the tumor issue for cancer therapy. The work may provide a new way for scientists to construct functional biomaterials with multiple applications via molecular self-assembly.

ß-Cyclodextrin modified Pt(II) metallacycle-based supramolecular hyperbranched polymer assemblies for DOX delivery to liver cancer cells.

Despite the widespread clinical application of chemotherapeutic anticancer drugs, their adverse side effects and inefficient performances remain ongoing issues. A drug delivery system (DDS) designed for a specific cancer may therefore overcome the drawbacks of single chemotherapeutic drugs and provide precise and synergistical cancer treatment by introducing exclusive stimulus responsiveness and combined chemotherapy properties. Herein, we report the design and synthesis of a supramolecular drug delivery assembly 1 constructed by orthogonal self-assembly technique in aqueous media specifically for application in liver cancer therapy. Complex 1 incorporates the ß-cyclodextrin host molecule-functionalized organoplatinum(II) metallacycle 2 with two specific stimulus-responsive motifs to the signaling molecule nitric oxide (NO), in addition to the three-armed polyethylene glycol (PEG) functionalized ferrocene 3 with redox responsiveness. With this molecular design, the particularly low critical aggregation concentration (CAC) of assembly 1 allowed encapsulation of the commercial anticancer drug doxorubicin (DOX). Controlled drug release was also achieved by morphological transfer via a sensitive response to the endogenous redox and NO stimuli, which are specifically related to the microenvironment of liver tumor cells. Upon combination of these properties with the anticancer ability from the platinum acceptor, in vitro studies demonstrated that DOX-loaded 1 is able to codeliver anticancer drugs and exhibit therapeutic effectiveness to liver tumor sites via a synergistic effect, thereby revealing a potential DDS platform for precise liver cancer therapeutics.

Platinum Metallacycle-Based Molecular Recognition: Establishment and Application in Spontaneous Formation of a [2]Rotaxane with Light-Harvesting Property.

Macrocyclic molecule-based host-guest systems, which provide contributions for the design and construction of functional supramolecular structures, have gained increasing attention in recent years. In particular, platinum(II) metallacycle-based host-guest systems provide opportunities for chemical scientists to prepare novel materials with various functions and structures due to the well-defined shapes and cavity sizes of platinum(II) metallacycles. However, the research on platinum(II) metallacycle-based host-guest systems has been given little attention. In this article, we demonstrate the host-guest complexation between a platinum(II) metallacycle and a polycyclic aromatic hydrocarbon molecule, naphthalene. Taking advantage of metallacycle-based host-guest interactions and the dynamic property of reversible Pt coordination bonds, a [2]rotaxane is efficiently prepared by employing a template-directed clipping procedure. The [2]rotaxane is further applied to the fabrication of an efficient light-harvesting system with multi-step energy transfer process. This work comprises an important supplement to macrocycle-based host-guest systems and demonstrates a strategy for efficient production of well-defined mechanically interlocked molecules with practical values.

BODIPY based Metal-Organic Macrocycles and Frameworks: Recent Therapeutic Developments.

Boron dipyrromethene, commonly known as BODIPY, based metal-organic macrocycles (MOCs) and metal-organic frameworks (MOFs) represent an interesting part of materials due to their versatile tunability of structure and functionality as well as significant physicochemical properties, thus broadening their applications in various scientific domains, especially in biomedical sciences. With increasing concern over the efficacy of cancer drugs versus quality of patient's life dilemma, scientists have been trying to fabricate novel comprehensive therapeutic strategies along with the discovery of novel safer drugs where research with BODIPY metal complexes has shown vital advancements. In this review, we have exclusively examined the articles involving studies related to light harvesting and photophysical properties of BODIPY based MOCs and MOFs, synthesized through self-assembly process, with a special focus on biomolecular interaction and its importance in anti-cancer drug research. In the end, we also emphasized the possible practical challenges involved during the synthetic process, based on our experience on dealing with BODIPY molecules and steps to overcome them along with their future potentials. This review will significantly help our fellow research groups, especially the budding researchers, to quickly and comprehensively get the near to wholesome picture of BODIPY based MOCs and MOFs and their present status in anti-cancer drug discovery.

An Organoplatinum(II) Metallacycle-Based Supramolecular Amphiphile and Its Application in Enzyme-Responsive Controlled Release.

Enzyme-responsive nanomaterials are emerging as important candidates for bioanalytical and biomedical applications due to their good biocompatibilities and sensitivities. However, the lack of promising operation platforms compatible with enzyme responsiveness greatly limits the scope and functionality of smart materials. Herein, we report the design and synthesis of a naphthalene-functionalized organoplatinum(II) metallacycle 1 by means of coordination-driven self-assembly, which is subsequently exploited as the organometallic platform to enable enzyme-responsive supramolecular materials. Specifically, a [2 + 2] self-assembled metallacycle 1 first self-assembles into nanosheets in aqueous solution, which can further transform into vesicles with the introduction of ß-cyclodextrin (ß-CD) because of the formation of a bola-type supramolecular amphiphile ß-CD-1. Interestingly, these vesicles show rare α-amylase responsiveness, as demonstrated by structurally transforming back into nanosheets after the addition of α-amylase to their solutions due to the enzyme-induced degradation of cyclodextrins. We also demonstrate the potential application of the self-assembled vesicles in amylase-responsive controlled release.

Host-Guest Encapsulation to Promote the Formation of a Multicomponent Trigonal-Prismatic Metallacage.

An inclusion complex of a trigonal-prismatic metallacage with two coronene guests was constructed by multicomponent coordination-driven self-assembly from a 90° platinum(II) acceptor [cis-Pt(PEt3)2(OTf)2], disodium terephthalate, and 2,4,6-tri(4-pyridyl)-1,3,5-triazine in the presence of excess coronene. This platinum(II)-based trigonal prism was found to be a highly matched host to simultaneously encapsulate two coronene molecules. The encapsulation of coronene can effectively promote the formation of a pure single-prismatic metallacage and can stabilize the self-assembled structure via strong π-π-stacking interactions between coronene and the metallacage.

Membrane intercalation-enhanced photodynamic inactivation of bacteria by a metallacycle and TAT-decorated virus coat protein.

Antibiotic resistance has become one of the major threats to global health. Photodynamic inactivation (PDI) develops little antibiotic resistance; thus, it becomes a promising strategy in the control of bacterial infection. During a PDI process, light-induced reactive oxygen species (ROS) damage the membrane components, leading to the membrane rupture and bacteria death. Due to the short half-life and reaction radius of ROS, achieving the cell-membrane intercalation of photosensitizers is a key challenge for PDI of bacteria. In this work, a tetraphenylethylene-based discrete organoplatinum(II) metallacycle (1) acts as a photosensitizer with aggregation-induced emission. It self-assembles with a transacting activator of transduction (TAT) peptide-decorated virus coat protein (2) through electrostatic interactions. This assembly (3) exhibits both ROS generation and strong membrane-intercalating ability, resulting in significantly enhanced PDI efficiency against bacteria. By intercalating in the bacterial cell membrane or entering the bacteria, assembly 3 decreases the survival rate of gram-negative Escherichia coli to nearly zero and that of gram-positive Staphylococcus aureus to ∼30% upon light irradiation. This study has wide implications from the generation of multifunctional nanomaterials to the control of bacterial infection, especially for gram-negative bacteria.

A self-assembled Ru-Pt metallacage as a lysosome-targeting photosensitizer for 2-photon photodynamic therapy.

Photodynamic therapy (PDT) is a treatment procedure that relies on cytotoxic reactive oxygen species (ROS) generated by the light activation of a photosensitizer. The photophysical and biological properties of photosensitizers are vital for the therapeutic outcome of PDT. In this work a 2D rhomboidal metallacycle and a 3D octahedral metallacage were designed and synthesized via the coordination-driven self-assembly of a Ru(II)-based photosensitizer and complementary Pt(II)-based building blocks. The metallacage showed deep-red luminescence, a large 2-photon absorption cross-section, and highly efficient ROS generation. The metallacage was encapsulated into an amphiphilic block copolymer to form nanoparticles to encourage cell uptake and localization. Upon internalization into cells, the nanoparticles selectively accumulate in the lysosomes, a favorable location for PDT. The nanoparticles are almost nontoxic in the dark, and can efficiently destroy tumor cells via the generation of ROS in the lysosomes under 2-photon near-infrared light irradiation. The superb PDT efficacy of the metallacage-containing nanoparticles was further validated by studies on 3D multicellular spheroids (MCS) and in vivo studies on A549 tumor-bearing mice.

Self-assembled ruthenium (II) metallacycles and metallacages with imidazole-based ligands and their in vitro anticancer activity.

Six tetranuclear rectangular metallacycles were synthesized via the [2+2] coordination-driven self-assembly of imidazole-based ditopic donor 1,4-bis(imidazole-1-yl)benzene and 1,3-bis(imidazol-1-yl)benzene, with dinuclear half-sandwich p-cymene ruthenium(II) acceptors [Ru2(µ-η4-oxalato)(η6-p-cymene)2](SO3CF3)2, [Ru2(µ-η4-2,5-dioxido-1,4-benzoquinonato)(η6-p-cymene)2](SO3CF3)2 and [Ru2(µ-η4-5,8-dioxido-1,4-naphtoquinonato)(η6-p-cymene)2](SO3CF3)2, respectively. Likewise, three hexanuclear trigonal prismatic metallacages were prepared via the [2+3] self-assembly of tritopic donor of 1,3,5-tri(1H-imidazol-1-yl)benzene with these ruthenium(II) acceptors respectively. Self-selection of the single symmetrical and stable metallacycle and cage was observed although there is the possibility of forming different conformational isomeric products due to different binding modes of these imidazole-based donors. The self-assembled macrocycles and cage containing the 5,8-dioxido-1,4-naphtoquinonato (donq) spacer exhibited good anticancer activity on all tested cancer cell lines (HCT-116, MDA-MB-231, MCF-7, HeLa, A549, and HepG-2), and showed decreased cytotoxicities in HBE and THLE-2 normal cells. The effect of Ru and imidazole moiety of these assemblies on the anticancer activity was discussed. The study of binding ability of these donq-based Ru assemblies with ctDNA indicated that the complex 9 with 180° linear 1 ligand has the highest bonding constant Kb to ctDNA.

Melanin-dot-mediated delivery of metallacycle for NIR-II/photoacoustic dual-modal imaging-guided chemo-photothermal synergistic therapy.

Discrete Pt(II) metallacycles have potential applications in biomedicine. Herein, we engineered a dual-modal imaging and chemo-photothermal therapeutic nano-agent 1 that incorporates discrete Pt(II) metallacycle 2 and fluorescent dye 3 (emission wavelength in the second near-infrared channel [NIR-II]) into multifunctional melanin dots with photoacoustic signal and photothermal features. Nano-agent 1 has a good solubility, biocompatibility, and stability in vivo. Both photoacoustic imaging and NIR-II imaging in vivo confirmed that 1 can effectively accumulate at tumor sites with good signal-to-background ratio and favorable distribution. Guided by precise dual-modal imaging, nano-agent 1 exhibits a superior antitumor performance and less severe side effects compared with a single treatment because of the high efficiency of the chemo-photothermal synergistic therapy. This study shows that nano-agent 1 provides a promising multifunctional theranostic platform for potential applications in biomedicine.

Host-guest complexation-mediated codelivery of anticancer drug and photosensitizer for cancer photochemotherapy.

Although platinum-based anticancer drugs prevail in cancer treatment, their clinical applications are limited by the severe side effects as well as their ineffectiveness against drug resistant cancers. A precise combination of photodynamic therapy (PDT) and chemotherapy can synergistically improve the therapeutic outcome and thereby may overcome drug resistance through a multipronged assault. Herein, we employ the well-defined cavity of a discrete organoplatinum(II) metallacage (M) to encapsulate octaethylporphine (OEP), a photosensitizer, forming a dual-functionalized system M⊃OEP that is wrapped into the hydrophobic core of the nanoparticles (MNPs) self-assembled from an amphiphilic diblock copolymer. Using a copper-free click reaction, a targeting ligand is conjugated on the surface of the MNPs, aiming to specifically deliver a chemotherapeutic drug and a photosensitizer to cancer cells. Benefiting from the enhanced permeability and retention effect and active targeting capability, high tumor accumulation of MNPs is achieved, leading to an improved therapeutic outcome and reduced side effects. In vivo studies demonstrate that the combination of chemotherapy and PDT exhibits a superior antitumor performance against a drug-resistant tumor model attributed to their synergistic anticancer efficacy.