Carrier-Free Nanoprodrug Mediating Laser-Activable Chemotherapeutic Immunomodulation against Cancer

Gemcitabine (GEM), an "old-school" chemotherapeutic agent, holds significant potential for repurposing due to its immunomodulatory properties, particularly in mitigating the immunosuppressive tumor microenvironment by depleting myeloid-derived suppressor cells and regulatory T cells. However, it is not regarded as an immunogenic agent, leaving a "cold" tumor state. Thus, we developed a carrier-free nanoprodrug that self-assembles from two zinc phthalocyanine (ZnPc)-based photosensitizer prodrugs, incorporating photodynamic therapy (PDT) to induce immunogenic cell death. A reactive oxygen species (ROS)-cleavable β-aminoacrylate linker (AA) was utilized to conjugate ZnPc and GEM, synthesizing the prodrug ZnPc-AA-GEM, which enables GEM release following ROS generation induced by PDT. Furthermore, the amphiphilic ZnPc-PEG enhances the stability and circulation time of the nanoprodrugs. These nanoprodrugs facilitate efficient tumor accumulation of GEM, activating its function through laser irradiation. Importantly, the combination of PDT and GEM increases tumor immunogenicity, enhancing effector T cell recruitment and mitigating tumor-associated immunosuppression, thereby amplifying the chemotherapeutic immunomodulatory effects of GEM. Comprehensive biosecurity evaluations indicated that carrier-free nanoprodrug exhibits minimal hemotoxicity and no significant adverse effects. Our study proposes a strategy that leverages traditional chemotherapeutics alongside advanced photodynamic approaches for more effective cancer treatment.