M1 macrophage membrane-engineered PLGA nanoparticles reprogram M2 tumor-associated macrophages to enhance anti-tumor immunity in breast cancer

Nanoparticles (NPs) are used as a suitable delivery system in cancer immunotherapy. Coating NPs with cell membranes can improve their therapeutic efficacy. Tumor-associated macrophages (TAMs) with a dominant phenotype of M2 and anti-inflammatory properties are found within the tumor microenvironment and contribute to tumor progression. Reprogramming TAMs toward a pro-inflammatory M1 phenotype can be a suitable approach to alter the tumor microenvironment and improve treatment outcomes. In this study, we synthesized poly(lactic-co-glycolic acid) (PLGA) NPs loaded with a TLR7/8 agonist (R848) and coated with M1 macrophage cell membranes (CM1), along with a cyclic dinucleotide (CDN) agonist (PLGA-CM1-CDN-R848 NPs), and their ability to reprogram M2-like macrophages was investigated using an in vitro model. PLGA-CM1-CDN-R848 NPs were preferentially taken up by M2-like macrophages and efficiently stimulated the pro-inflammatory cytokines (IL-6, TNF-α, and iNOS) as well as the STING pathway (IFN-β). The reprogrammed macrophages induced apoptosis and cell cycle arrest (G0/G1 and G2/M phases) in 4T1 breast cancer cells. In conclusion, the PLGA-CM1-CDN-R848 NPs formulation represents a promising strategy for breast cancer immunotherapy by targeting M2 TAMs within the TME and reprogramming them toward the M1 phenotype.