An engineered self-biomineralized oncolytic adenovirus induces effective antitumor immunity and synergizes with immune checkpoint blockade.

Oncolytic adenoviruses (oADV) are promising cancer treatment agents. However, in vivo hepatic sequestration and the host immunological response against the agents limit the therapeutic potential of oADVs. Herein, we present a combined, rational design method for improving oADV infection efficiency, immunogenicity, and treatment efficacy by self-biomineralization. We integrated the biomimetic nucleopeptide W6p into the capsid of oADV using reverse genetics, allowing calcium phosphate mineralization to be biologically induced on the surface of oADV under physiological conditions, resulting in a mineral exterior. This self-biomineralized, modified oADV (oADV-W6-CaP) enhanced infection efficiency and therapeutic efficacy in coxsackie and adenovirus receptor (CAR)-negative cancer cells while protecting them against neutralization by pre-existing neutralizing antibodies. In subcutaneous mouse tumor models, systemic injection of oADV-W6-CaP demonstrated improved antitumor effectiveness, which was associated with increased T-cell infiltration and CD8+ T-cell activation. In addition, the anticancer immune response elicited by oADV-W6-CaP was dependent on CD8+ T cells, which mediated long-term immunological memory and systemic antitumor immunity against the same tumor. Finally, the addition of PD-1 or CD47 inhibition boosted the anticancer effects of oADV-W6-CaP and raised the rate of complete tumor clearance in tumor-bearing animals. The self-biomineralized oADV shifted the suppressive tumor microenvironment from a "cold" state to a "hot" state and synergized with immune checkpoint blockade to exert outstanding tumoricidal effects, demonstrating promising potential for cancer immunotherapy.

cGAS-activated endothelial cell-T cell cross-talk initiates tertiary lymphoid structure formation.

Aberrant activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway causes autoimmunity in humans and mice; however, the exact mechanism by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology is still not fully understood. Here, we used a cGAS knockin (KI) mouse model that develops systemic autoimmunity. In the lungs of cGAS-KI mice, blood vessels were enclosed by organized lymphoid tissues that resemble tertiary lymphoid structures (TLSs). Cell-intrinsic cGAS induction promoted up-regulation of CCR5 in CD8+ T cells and led to CCL5 production in vascular endothelial cells. Peripheral CD8+ T cells were recruited to the lungs and produced CXCL13 and interferon-γ. The latter triggered endothelial cell death, potentiated CCL5 production, and was essential for TLS establishment. Blocking CCL5 or CCR5, or depleting CD8+ T cells, impaired TLS formation. cGAS-mediated TLS formation also enhanced humoral and antitumor responses. These data demonstrate that cGAS signaling drives a specialized lymphoid structure that underlies autoimmune tissue pathology.

Organoid-Based Assessment of Metal-Organic Framework (MOF) Nanomedicines for Ex Vivo Cancer Therapy.

Nanomaterials have been extensively exploited in tumor treatment, leading to numerous innovative strategies for cancer therapy. While nanomedicines present immense potential, their application in cancer therapy is characterized by significant complexity and unpredictability, especially regarding biocompatibility and anticancer efficiency. These considerations underscore the essential need for the development of ex vivo research models, which provide invaluable insights and understanding into the biosafety and efficacy of nanomedicines in oncology. Fortunately, the emergence of organoid technology offers a novel approach to the preclinical evaluation of the anticancer efficacy of nanomedicines in vitro. Hence, in this study, we constructed intestine and hepatocyte organoid models (Intestine-orgs and Hep-orgs) for assessing intestinal and hepatic toxicity at the microtissue level. We utilized three typical metal-organic frameworks (MOFs), ZIF-8, ZIF-67, and MIL-125, as nanomedicines to further detect their interactions with organoids. Subsequently, the MIL-125 with biocompatibility loaded methotrexate (MTX), forming the nanomedicine (MIL-125-PEG-MTX), indicated a high loading efficiency (82%) and a well-release capability in an acid microenvironment. More importantly, the anticancer effect of the nanomedicine was investigated using an in vitro patient-derived organoids (PDOs) model, achieving inhibition rates of 48% and 78% for PDO-1 and PDO-2, respectively, demonstrating that PDOs could predict clinical response and facilitate prospective therapeutic selection. These achievements presented great potential for organoid-based ex vivo models for nano theragnostic evaluation in biosafety and function.

Outer membrane vesicle-wrapped manganese nanoreactor for augmenting cancer metalloimmunotherapy through hypoxia attenuation and immune stimulation.

Tumor hypoxia, high oxidative stress, and low immunogenic create a deep-rooted immunosuppressive microenvironment, posing a major challenge to the therapeutic efficiency of cancer immunotherapy for solid tumor. Herein, an intelligent nanoplatform responsive to the tumor microenvironment (TME) capable of hypoxia relief and immune stimulation has been engineered for efficient solid tumor immunotherapy. The MnO2@OxA@OMV nanoreactor, enclosing bacterial-derived outer membrane vesicles (OMVs)-wrapped MnO2 nanoenzyme and the immunogenic cell death inducer oxaliplatin (OxA), demonstrated intrinsic catalase-like activity within the TME, which effectively catalyzed the endogenous H2O2 into O2 to enable a prolonged oxygen supply, thereby alleviating the tumor's oxidative stress and hypoxic TME, and expediting OxA release. The combinational action of OxA-caused ICD effect and Mn2+ from nanoreactor enabled the motivation of the cGAS-STING pathway to significantly improve the activation of STING and dendritic cells (DCs) maturation, resulting in metalloimmunotherapy. Furthermore, the immunostimulant OMVs played a crucial role in promoting the infiltration of activated CD8+T cells into the solid tumor. Overall, the nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy. STATEMENT OF SIGNIFICANCE: A tailor-made nanoreactor was fabricated by enclosing bacterial-derived outer membrane vesicles (OMVs) onto MnO2 nanoenzyme and loading with immunogenic cell death inducer oxaliplatin (OxA) for tumor metalloimmunotherapy. The nanoreactor possesses intrinsic catalase-like activity within the tumor microenvironment, which effectively enabled a prolonged oxygen supply by catalyzing the conversion of endogenous H2O2 into O2, thereby alleviating tumor hypoxia and expediting OxA release. Furthermore, the TME-responsive release of nutritional Mn2+ sensitized the cGAS-STING pathway and collaborated with OxA-induced immunogenic cell death (ICD). Combing with immunostimulatory OMVs enhances the uptake of nanoreactors by DCs and promotes the infiltration of activated CD8+T cells. This nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy.

DOX-loaded hydroxyapatite nanoclusters for colorectal cancer (CRC) chemotherapy: Evaluation based on the cancer cells and organoids.

It is meaningful to find suitable in vitro models for preclinical toxicology and efficacy evaluation of nanodrugs and nanocarriers or drug screening and promoting clinical transformation of nanocarriers. The emergence and development of organoids technology provide a great possibility to achieve this goal. Herein, we constructed an in vitro 3D organoid model to study the inhibitory effect of nanocarriers on colorectal cancer. And designed hydroxyapatite nanoclusters (c-HAP) mediated by polydopamine (PDA) formed under alkaline conditions (pH 9.0), then used c-HAP to load DOX (c-HAP/DOX) as nanocarrier for improved chemotherapy. In vitro, drug release experiments show that c-HAP/DOX has suitable responsive to pH, can be triggered to the facile release of DOX in a slightly acidic environment (pH 6.0), and maintain specific stability in a neutral pH value (7.4) environment. c-HAP/DOX showed an excellent antitumor effect in the two-dimensional (2D) cell model and three-dimensional (3D) patient-derived colon cancer organoids (PDCCOs) model. In addition, c-HAP/DOX can release a sufficient amount of DOX to produce cytotoxicity in a slightly acidic environment, entering efficiently into the colorectal cancer cells caused endocytosis and induced apoptosis. Therefore, organoids can serve as an effective in vitro model to present the structure and function of colorectal cancer tissues and be used to evaluate the efficacy of nanocarriers for tumors.

Time-varying characteristics of the induced membrane and its effects on bone defect repair.

PURPOSE: This study intended to determine the properties of induced membranes after various periods of polymethyl methacrylate (PMMA) retention and the effect of different retention intervals on subsequent defect repair. METHODS: Model of a critical bone defect in rabbits was prepared to obtain the induced membrane. For varying intervals of spacer insertion (2, 4, 6, 8, 12, 16, and 20 weeks postoperatively), angiogenesis, osteogenesis, and MSC-related properties were analyzed by immunohistochemistry and western-blot. Furthermore, 2, 4, 6, and 8 weeks after PMMA insertion, bone grafting was performed. Characteristics of defect repair were analyzed by X-ray and micro-CT analysis. RESULTS: The induced membrane displayed angiogenesis, osteogenesis, and MSC-related properties from the 2- to 20-week intervals. Quantitation of protein expression (RUNX2, ALP, VEGF, TGF-beta, OCT4, and STRO1) revealed that selected proteins gradually rose to a high level at 4-8 weeks postoperatively and then decreased to a low level over a long time period. Following bone grafting, the most new bone formation was in the group when grafting was performed at 4 weeks, followed by the groups at 2 and 6 weeks, with the least in the group at 8 weeks. CONCLUSION: The induced membrane displays angiogenesis, osteogenesis, and MSC-related properties from the 2- to 20-week intervals. These were increased to a peak level at 4-8 weeks postoperatively and then gradually decreased. The optimal timing for bone grafting at the second stage in the presented model was 4 weeks after PMMA insertion.

Nanomaterial-assisted CRISPR gene-engineering - A hallmark for triple-negative breast cancer therapeutics advancement.

Triple-negative breast cancer (TNBC) is the most violent class of tumor and accounts for 20-24% of total breast carcinoma, in which frequently rare mutation occurs in high frequency. The poor prognosis, recurrence, and metastasis in the brain, heart, liver and lungs decline the lifespan of patients by about 21 months, emphasizing the need for advanced treatment. Recently, the adaptive immunity mechanism of archaea and bacteria, called clustered regularly interspaced short palindromic repeats (CRISPR) combined with nanotechnology, has been utilized as a potent gene manipulating tool with an extensive clinical application in cancer genomics due to its easeful usage and cost-effectiveness. However, CRISPR/Cas are arguably the efficient technology that can be made efficient via organic material-assisted approaches. Despite the efficacy of the CRISPR/Cas@nano complex, problems regarding successful delivery, biodegradability, and toxicity remain to render its medical implications. Therefore, this review is different in focus from past reviews by (i) detailing all possible genetic mechanisms of TNBC occurrence; (ii) available treatments and gene therapies for TNBC; (iii) overview of the delivery system and utilization of CRISPR-nano complex in TNBC, and (iv) recent advances and related toxicity of CRISPR-nano complex towards clinical trials for TNBC.

Constructing Injectable Bone-Forming Units by Loading a Subtype of Osteoprogenitors on Decellularized Bone Matrix Powders for Bone Regeneration.

Bone defects resulting from trauma or tumor are one of the most challenging problems in clinical settings. Current tissue engineering (TE) strategies for managing bone defects are insufficient, owing to without using optimal osteoconductive material and seeding cells capable of superior osteogenic potential; thus their efficacy is instable. Herein, a novel TE strategy was developed for treating bone defects. First, the decellularized bone matrix (DBM) was manufactured into powders, and these DBM powders preserved the ultrastructural and compositional properties of native trabecular bone, are non-cytotoxic and low-immunogenic, and are capable of inducing the interacted stem cells differentiating into osteogenic lineage. Then, a subtype of osteoprogenitors was isolated from mouse long bones, and its high osteogenic potential was identified in vitro. After that, we constructed a "bone-forming unit" by seeding the special subtype of osteoprogenitors onto the DBM powders. In vivo performance of the "bone-forming units" was determined by injecting into the defect site of a mouse femoral epiphysis bone defect model. The results indicated that the "bone-forming unit" was capable of enhancing bone defect healing by regulating new bone formation and remodeling. Overall, the study establishes a protocol to construct a novel "bone-forming unit," which may be an alternative strategy in future bone TE application.

A biomineralized Prussian blue nanotherapeutic for enhanced cancer photothermal therapy.

Photothermal therapy is a promising tumor ablation technique that converts light into heat energy to kill cancer cells. Prussian blue (PB), a biocompatible photothermal reagent, has been widely explored for cancer treatment. However, the translational potential of PB is severely hampered by its low photothermal conversion efficiency (PCE) and poor stability. To tackle these issues, we adopted the biomineralization modality where PB was integrated with calcium phosphate (CaP) through the binding between calcium ions and PB. The mineralized PB (CaP&PB) demonstrated significantly improved PCE (40.2%), resulting from a calcium-induced bandgap-narrowing effect, and exhibited superior suspension stability. Using a 4T1 orthotopic breast cancer BALB/c mouse model, we observed that mineralized PB showed a significant temperature increase within the tumor, which led to better tumoricidal activity compared with CaP and PB when identical NIR treatment was applied. These achievements demonstrated the success of introducing calcium phosphate into Prussian blue by biomineralization to improve the PCE and stability of photothermal reagents, suggesting an alternative translational strategy for enhanced cancer photothermal therapy.

Manganese Phosphate-Doxorubicin-Based Nanomedicines Using Mimetic Mineralization for Cancer Chemotherapy.

Inorganic nanomaterials showed great potential as drug carriers for chemotherapeutics molecules due to their biocompatible physical and chemical properties. A manganese-based inorganic nanomaterial manganese phosphate (MnP) had become a new drug carrier in cancer therapy. However, the approach for manganese phosphate preparation and drug integration is still confined in complex methods. Inspired by mimetic mineralization, we proposed a "one-step" method for the preparation of manganese phosphate-doxorubicin (DOX) nanomedicines (MnP-DOX) by manganese ion and DOX complexation. The structural characterization results revealed that the prepared MnP-DOX nanocomplexes were homogeneous with controlled sizes and shapes. More importantly, the MnP-DOX nanocomposites could significantly induce cancer inhibition in vitro and in vivo. The results indicated that the drug molecules were integrated into MnP nanocarriers by mimetic mineralization, which not only prevented the premature release of the drug but also reduced excessive modification. Moreover, the designed MnP-DOX complex showed high loading efficacy and pH-dependent degradation leading to drug release, achieving high efficiency for cancer chemotherapy in vitro and in vivo via a facile process. These achievements presented an approach to construct the manganese phosphate-based chemotherapy nanomedicines by mimetic mineralization for cancer therapy.

siRNA-Loaded Hydroxyapatite Nanoparticles for KRAS Gene Silencing in Anti-Pancreatic Cancer Therapy.

Pancreatic carcinoma (PC) is greatly induced by the KRAS gene mutation, but effective targeted delivery for gene therapy has not existed. Small interfering ribonucleic acid (siRNA) serves as an advanced therapeutic modality and holds great promise for cancer treatment. However, the development of a non-toxic and high-efficiency carrier system to accurately deliver siRNA into cells for siRNA-targeted gene silencing is still a prodigious challenge. Herein, polyethylenimine (PEI)-modified hydroxyapatite (HAp) nanoparticles (HAp-PEI) were fabricated. The siRNA of the KRAS gene (siKras) was loaded onto the surface of HAp-PEI via electrostatic interaction between siRNA and PEI to design the functionalized HAp-PEI nanoparticle (HAp-PEI/siKras). The HAp-PEI/siKras was internalized into the human PC cells PANC-1 to achieve the maximum transfection efficiency for active tumor targeting. HAp-PEI/siKras effectively knocked down the expression of the KRAS gene and downregulated the expression of the Kras protein in vitro. Furthermore, the treatment with HAp-PEI/siKras resulted in greater anti-PC cells' (PANC-1, BXPC-3, and CFPAC-1) efficacy in vitro. Additionally, the HAp-PEI exhibited no obvious in vitro cytotoxicity in normal pancreatic HPDE6-C7 cells. These findings provided a promising alternative for the therapeutic route of siRNA-targeted gene engineering for anti-pancreatic cancer therapy.

Three-dimensional mapping of distal humerus fracture.

BACKGROUND: Distal humerus fractures (DHFs) constitute one-third of elbow fractures approximately. In this study, we aim to define and analyze the fracture lines and morphological features of DHFs using mapping technique. METHODS: One hundred and two DHFs were retrospectively reviewed. All the computed tomography (CT) data were used to manually reconstruct and virtually reduce the DHF fragments to fit a standard 3D model. Smooth curves were depicted accurately onto the surface of the template to represent the fracture lines. All the curves were overlapped onto the model to create the 3D fracture map and heat map. RESULTS: Our analysis was based on 102 CT images of DHFs, contributed by 59 male and 43 female patients (mean age, 46 years; range, 18-93 years), and included 15 type A, 25 type B, and 62 type C fractures. On mapping, the hot zones were located in the radial fossa, coronoid fossa, olecranon fossa, and the external part of the trochlear. Conversely, the cold zones were noted in medial condyle, the medial side of the trochlear, and the anterolateral area on the supracondylar ridge. CONCLUSIONS: Our study firstly shows the fracture lines and morphological features of distal humeral fractures by three-dimensional mapping technology. Distal humerus fracture lines are characteristic and highly related to the micro-architecture difference of distal humerus, which may provide some guidance for the treatment plan selection and surgical fixation design.

Multivalent effects of heptamannosylated ß-cyclodextrins on macrophage polarization to accelerate wound healing.

Macrophages have high plasticity and heterogeneity, and can suppress or mediate inflammation, depending on their cytokine secretion and phenotype. Regulating macrophage polarization into its M2 phenotype has a remarkable effect on inflammatory inhibition, inducing the regeneration of injured tissues. Here, we synthesized two heptamannosylated ß-cyclodextrin derivatives (CD-Man7 and C3-CD-Man7) and demonstrated that their multivalent mannose ligands could induce M2 macrophage polarization to accelerate wound healing. Unlike hydrophilic CD-Man7, amphiphilic C3-CD-Man7 can self-assemble to form nanoparticles (CD-Man-NPs) in aqueous solution. Further, in vitro results confirmed that multivalent mannose ligands of either CD-Man7 or CD-Man-NPs stimulated RAW264.7 macrophages to differentiate into the M2 phenotype, which promoted fibroblast migration via a paracrine mechanism. In vivo results confirmed that both CD-Man7 and CD-Man-NPs reduced the inflammatory response in wound tissue and accelerated wound healing. The present study demonstrates multivalent effects of CD-Man7 and CD-Man-NPs on M2 macrophage polarization, indicating the therapeutic potential of these ß-cyclodextrin glycoconjugates in the treatment of inflammatory diseases and wound healing.

Mg(OH)2 nanoparticles enhance the antibacterial activities of macrophages by activating the reactive oxygen species.

Infection often causes disastrous consequences in all fields of clinical medicine, especially orthopedics. Hence, critical efforts are being made to engineer novel nanomaterials for the treatment of orthopedic infections due to the high biocompatibility and antibacterial properties they possess. The purpose of this study was to investigate the antibacterial effects of magnesium hydroxide (Mg(OH)2 ) nanoparticles (NPs) in vitro and determine their possible mechanisms of action. In this study, Escherichia coli was selected as the pathogenic bacteria and it was found that Mg(OH)2 NPs significantly inhibited the growth of E. coli by promoting nucleic acid leakage, inhibiting protein synthesis, and suppressing the metabolic activity. The minimum inhibitory concentration for these bacteria was determined to be 4.4 µg/ml. In vitro flow cytometry and immunofluorescence tests indicated that Mg(OH)2 NPs induced the macrophages to generate reactive oxygen species to kill the bacteria. To understand the mechanisms involved in this process, western blotting was performed and it was found that Mg(OH)2 NPs activated the phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/Akt) signaling pathway of macrophages to enhance their phagocytosis with no obvious cytotoxicity. Thus, Mg(OH)2 NPs are a suitable choice to develop promising agents or coating materials for the treatment of clinically widespread infections in view of their safety, biocompatibility, and powerful antibacterial properties.

Hierarchical nano-to-molecular disassembly of boron dipyrromethene nanoparticles for enhanced tumor penetration and activatable photodynamic therapy.

The development of activatable photosensitizers (PSs) is of particular interest for achieving tumor photodynamic therapy (PDT) with minimal side effects. However, the in vivo applications of PSs are limited by complex physiological and biological delivery barriers. Herein, boron dipyrromethene (BDP)-based nanoparticles are developed through the self-assembly of a multifunctional "one-for-all" building block for enhanced tumor penetration and activatable PDT. The nanoparticles show excellent colloidal stability and long circulation lifetime in blood. Once they reach the tumor site, the first-stage size reduction occurs due to the hydrolysis of the Schiff base bond between polyethylene glycol and the cyclic Arg-Gly-Asp peptide in the acidic tumor microenvironment (pH~6.5), facilitating tumor penetration and specific recognition by cancer cells overexpressing integrin ανß3 receptors. Upon the endocytosis by cancer cells, the second-stage size reduction is triggered by more acidic pH in lysosomes (pH~4.5). Importantly, the protonated diethylamino groups can block photoinduced electron transfer from the amine donor to the excited PSs and accelerate complete disassembly of the nanoparticles into single PS molecule, with the recovery of the fluorescence and photoactivity for efficient PDT. This study presents a smart PS delivery strategy involving acidity-triggered hierarchical disassembly from the nano to molecular scale for precise tumor PDT.

Inorganic material based macrophage regulation for cancer therapy: basic concepts and recent advances.

Macrophages with the M1 phenotype are a type of immune cell with exciting prospects for cancer therapy; however, when these macrophages infiltrate into tumours, many of them are induced by the tumour microenvironment to transform into the M2 type, which can enable tumour defence against external therapeutic strategies, assisting in tumour development. Macrophages have strong plasticity and functional heterogeneity, and their phenotypic transformation is complex and still poorly understood in relation to cancer therapy. Recent material advances in inorganic nanomaterials, especially inorganic elements in vivo, have accelerated the development of macrophage regulation-based cancer treatments. This review summarizes the basics of recent research on macrophage phenotype transformation and discusses the current challenges in macrophage type regulation. Then, the current achievements involving inorganic material-based macrophage regulation and the related anticancer effects of induced macrophages and their extracellular secretions are reviewed systematically. Importantly, inorganic nanomaterial-based macrophage phenotype regulation is flexible and can be adapted for different types of cancer therapies, presenting a possible novel approach for the generation of immune materials for cancer therapy.

Discovery of A031 as effective proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader for the treatment of prostate cancer.

Androgen receptor (AR) is an effective therapeutic target for the treatment of prostate cancer. We report herein the design, synthesis, and biological evaluation of highly effective proteolysis targeting chimeras (PROTAC) androgen receptor (AR) degraders, such as compound A031. It could induce the degradation of AR protein in VCaP cell lines in a time-dependent manner, achieving the IC 50 value of less than 0.25 µM. The A031 is 5 times less toxic than EZLA and works with an appropriate half-life (t 1/2) or clearance rate (Cl). Also, it has a significant inhibitory effect on tumor growth in zebrafish transplanted with human prostate cancer (VCaP). Therefore, A031 provides a further idea of developing novel drugs for prostate cancer.

Biosilicified oncolytic adenovirus for cancer viral gene therapy.

Oncolytic adenoviruses (OAs) have shown great potential for cancer viral gene therapy in clinical studies. To date, clinical trials have shown that the curative efficacy of OAs is still limited by hepatic sequestration and preexisting neutralizing antibodies (nAbs), which decrease the accumulation of the OAs in tumors. Herein, with the biosilicification method, we encapsulated an OA encoding the anticancer gene Trail (OA-Trail) with silica, which significantly improved virus distribution and tumor inhibition. In vitro and in vivo results indicated that compared with the native OA, biosilicified OA-Trail (OA-Trail@SiO2) showed significantly reduced viral clearance in the liver and evaded nAb degradation, inducing an efficacious anticancer effect under the premise of biocompatibility. These achievements present an alternative strategy involving biosilicification for enhanced OA-based cancer gene therapy.

Multifunctional nanoparticles as photosensitizer delivery carriers for enhanced photodynamic cancer therapy.

Photodynamic therapy (PDT) is an emerging cancer treatment combining light, oxygen, and a photosensitizer (PS) to produce highly cytotoxic reactive oxygen species that cause cancer cell death. However, most PSs are hydrophobic molecules that have poor water solubility and cannot target tumor tissues, causing damage to normal tissues and cells during PDT. Thus, there is a substantial demand for the development of nanocarrier systems to achieve targeted delivery of PSs into tumor tissues and cells. This review summarizes the research progress in PS delivery systems for PDT treatment of tumors and focuses on the recent design and development of multifunctional nanoparticles as PS delivery carriers for enhanced PDT. These multifunctional nanoparticles possess unique properties, including tunable particle size, changeable shape, stimuli-responsive PS activation, controlled PS release, and hierarchical targeting capability. These properties can increase tumor accumulation, penetration, and cellular internalization of nanoparticles to achieve PS activation and/or release in cancer cells for enhanced PDT. Finally, recent developments in multifunctional nanoparticles for tumor-targeted PS delivery and their future prospects in PDT are discussed.