Multifunctional poly(amino acid) nanomedicine modulates macrophage polarization for osteosarcoma immunotherapy

In tumor microenvironments (TMEs), M1 macrophages suppress tumors through cytotoxic molecule secretion and antibody-dependent cell-mediated cytotoxicity, whereas M2 macrophages promote tumor proliferation via TGF-β and Arg1 release. However, existing macrophage-modulating strategies remain suboptimal owing to insufficient M2 suppression and inefficient M1 induction. To address this limitation, a multifunctional nanomedicine (PM-DPA/R848) is developed by loading the TLR7/8 agonist resiquimod (R848) into a nanocarrier composed of poly(L-methionine) (PM) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)-alendronate (DSPE-PEG-ALN, DPA). The PM component reduces intracellular reactive oxygen species (ROS) levels in macrophages by 63.8%, resulting in a 31.1% reduction in M2-polarized macrophages compared with the Control group. Concurrently, R848 release induces M1 reprogramming through activation of the MYD88/IRAK1/NF-κB pathway, increasing the M1 macrophage population by 1.4-fold. Moreover, DPA enhances intratumoral drug accumulation in vivo, and PM-DPA/R848 achieves a 77% tumor suppression rate. Thus, PM-DPA/R848 acts as a precision nanoformulation that synergistically suppresses M2 macrophages and promotes M1 polarization, providing a promising strategy for osteosarcoma immunotherapy.