pH-Activated Nanoplatform Derived from M1 Macrophages' Exosomes for Photodynamic and Ferroptosis Synergistic Therapy to Augment Cancer Immunotherapy.

Combining nanomedicine with immunotherapy offers a promising and potent cancer treatment strategy; however, improving the effectiveness of the antitumor immune response remains challenging. A "cold" tumor microenvironment (TME) is a marked factor affecting the efficacy of immunotherapy. Herein, intracellular-acidity-activatable dynamic nanoparticles (NPs) were designed for precision photodynamic immunotherapy and ferroptosis in cancer. M1 macrophage-derived exosomes (Mex) were constructed to coassemble the photosensitizer SR780, Fe³⁺, and the antioxidant enzyme catalase (CAT). By further modifying the RS17 peptides on the NPs, we increased their tumor-targeting capability and blocked the CD47-signal regulatory protein checkpoint, enabling macrophages to effectively phagocytose tumor cells. With proper particle size and dual targeting, including homologous targeting and RS17 targeting, FeSR780@CAT@Mex-RS17 NPs were able to accumulate effectively at the tumor site. These NPs can deliver exogenous CAT to relieve the hypoxic TME and enhance the therapeutic effects of photodynamic therapy. SR780 triggered photodynamic therapy to produce reactive oxygen species and induced immunogenic cell death to release danger-associated molecular patterns. In combination with Fe²⁺-induced ferroptosis, long-term immunotherapeutic effects can be obtained by reprogramming "cold" TMEs into "hot" TMEs. Upon laser irradiation, the designed FeSR780@CAT@Mex-RS17 NPs exert potent antitumor efficacy against both the Lewis lung carcinoma subcutaneous xenograft tumor model and lung orthotopic and liver metastasis models. The NPs suppressed the growth of the primary tumor while inhibiting liver metastasis, thereby exhibiting great potential for antitumor immunotherapy.