Mitochondria-Targeted HA-Coated Nanosystem for ROS/CO Generation and Metabolic Reprogramming to Enhance Tumoricidal Macrophage Polarization

Tumor-associated macrophage (TAM) polarization is related to mitochondrial function, stability, and ROS production. The development of a mitochondria-targeted nanosystem with immunomodulatory impact on TAM repolarization is crucial for macrophage-targeted immunotherapy. First, zirconium(IV) coordinated with tetra-kis(4-caboxyphenyl) porphyrin to synthesize PCN-224, which encapsulated CO-releasing molecule 401 (CORM-401) via the hollow structures (PCN-CORM), and then, an amphiphilic copolymer containing triphenylphosphine (TPP) was synthesized to load PCN-CORM via self-assembly and surface-coated with hyaluronic acid (HA) to obtain the mitochondria-targeted nanosystem (HA@MR@PCN-CORM). Mediated by HA and TPP motifs, HA@MR@PCN-CORM efficiently targeted mitochondria of TAMs via HA-CD44 interaction and re-exposed TPP groups by digesting HA and caused reactive oxygen species (ROS) and carbon dioxide (CO) storm under a laser irradiation of 660 nm (20 mW cm^-2), and the killing rate of M2-like TAMs reached 66.8% at a PCN-224 concentration of 15 μg/mL. Moreover, HA@MR@PCN-CORM, through depletion of GSH, inhibition of glutamine metabolism, and metabolic reprogramming, resulted in an increased ratio of M1/M2-type TAMs from 0.29 to 1.20 and an in vivo tumor volume inhibition rate of 93.4% with synergistically enhanced infiltration of CD3⁺/CD4⁺, CD3⁺/CD8⁺ T lymphocytes, and DCs in tumor tissues. The nanosystem was exhibited as a promising strategy for depletion and modulation of TAMs in an immunosuppressive tumor microenvironment for antitumor therapy.