MOF@COF Nanocapsules Enhance Soft Tissue Sarcoma Treatment: Synergistic Effects of Photodynamic Therapy and PARP Inhibition on Tumor Growth Suppression and Immune Response Activation

Abstract Soft tissue sarcomas (STS) are highly malignant tumors with limited treatment options owing to their heterogeneity and resistance to conventional therapies. Photodynamic therapy (PDT) and poly‐ADP‐ribose polymerase (PARP) inhibitors (PARPi) have shown potential for STS treatment, with PDT being effective for sarcomas located on the extremities and body surface and PARPi targeting defects in homologous recombination repair. To address the limitations of PDT and harness the potential of PARPi, herein, a novel therapeutic approach for STS treatment combining nanocapsules bearing integrated metal–organic frameworks (MOFs) and covalent organic frameworks (COFs), i.e., MOF@COF, with PDT and PARPi is proposed. Nanocapsules are designed, referred to as ZTN@COF@poloxamer, which contain a Zr‐based MOF and tetrakis (4‐carbethoxyphenyl) porphyrin as a photosensitizer, are coated with a COF to improve the sensitizing properties, and are loaded with niraparib to inhibit DNA repair. Experiments demonstrate that this new nanocapsules treatment significantly inhibits STS growth, promotes tumor cell apoptosis, exhibits high antitumor activity with minimal side effects, activates the immune response of the tumor, and inhibits lung metastasis in vivo. Therefore, MOF@COF nanocapsules combined with PARPi offer a promising approach for STS treatment, with the potential to enhance the efficacy of PDT and prevent tumor recurrence.