Biomimetic lipid nanoparticles for macrophage reprogramming in cancer immunotherapy

Tumor associated macrophages (TAMs) predominantly exhibit an immunosuppressive M2 like phenotype within the tumor microenvironment (TME), hindering the efficacy of cancer immunotherapy. To address this, we developed a dual biomimetic macrophage targeting lipid nanoparticle (Mac LNP) platform for robust M2 to M1 reprogramming. By integrating triglycerides and phosphatidylserine to mimic chylomicrons and apoptotic bodies, respectively, the Mac LNP achieved superior selectivity for macrophages over non-target cells. This platform co-encapsulated a TLR9 agonist (CpG-ODN) and STAT3 siRNA to synergistically drive M1 polarization while silencing the master transcription factor that sustains the M2 state. In a 4 T1 syngeneic breast cancer model, intratumoral administration of Mac LNPs significantly suppressed tumor growth and remodeled the immune landscape, as evidenced by a markedly increased M1/M2 ratio and enhanced infiltration of cytotoxic CD8⁺ T cells. Cross-model validation in an independent CT26 murine colorectal cancer model further confirmed the tumor-agnostic applicability of this platform. Our findings establish the Mac LNP system as a precision framework for macrophage targeted RNA therapeutics, effectively modulating innate immunity to overcome the immunosuppressive barriers of the TME.