Oxidation-Responsive PolyMOF Nanoparticles for Combination Photodynamic-Immunotherapy with Enhanced STING Activation

Stimulator of interferon genes (STING) activation by STING agonists has been recognized as one of the potent and promising immunotherapy strategies. However, the immunosuppressive tumor microenvironment always hinders the therapeutic efficacy of cancer immunotherapy. In this report, we present polymeric metal-organic framework (PMOF) nanoparticles (NPs) for the combination of photodynamic therapy (PDT) and enhanced STING activation to improve the immunotherapeutic efficacy. The PMOF NPs with poly(ethylene glycol) (PEG) shells were obtained via coordination between the block copolymer ligand PEG-b-PABDA consisting of 1,4-bezenedicarboxylic acid-bearing polyacrylamide (PABDA), meso-tetra(carboxyphenyl)porphyrin (TCPP), thioketal diacetic acid, and zirconyl chloride. Subsequently, the STING agonist SR-717 was loaded into the porous structure of PMOF to obtain SR@PMOF NPs which show excellent stability under the physiological conditions. After intravenous injection and tumor accumulation, light irradiation on the tumor sites results in efficient singlet oxygen (¹O₂) production from TCPP and cellular apoptosis to release fragmented DNA and tumor-associated antigens. Simultaneously, thioketal bonds can be broken by ¹O₂ to destroy the PMOF structure and rapidly release SR717. SR-717 and PDT synergistically enhance the antitumor immunity via combination photodynamic-immunotherapy due to reversal of the immunosuppressive tumor microenvironment and enhanced endogenous STING activation, which can suppress the growth of the primary and distant tumors efficiently. The oxidation-responsive SR@PMOF NPs represent a promising delivery system of STING agonists and efficient PDT NPs for simultaneous suppression of the primary and metastatic tumors via the rational combination of PDT and enhanced STING activation.