Enhancing tumor immunotherapy with smart nanoparticles for reprogramming macrophages and blocking the CD47/Sirpα pathway

Immunotherapy has significantly advanced cancer treatment, but the tumor immune microenvironment (TIME) often remains immunosuppressive, limiting therapeutic efficacy. Tumor-associated macrophages (TAMs), particularly M2-like macrophages, play a crucial role in promoting tumor growth and immune evasion. Our study introduces a novel approach using dual-targeted ZrMOF/C@P nanoparticles, smartly engineered with cell membrane coating and enzyme responsiveness, to effectively modulate TAMs. These nanoparticles are synthesized and loaded with 2', 3'-cGAMP, a STING agonist, and encapsulated in a peptide-expressed macrophage membrane (PMM) featuring Pep20, MMP2, and M2pep. <i>In vitro</i>, they activate the STING pathway in M2-like macrophages and reprogram them into M1-like macrophages. Smart ZrMOF/C@P is found to accumulate at the tumor even 72 h post-injection. In CT26 and 4T1 tumor models show that smart ZrMOF/C@P not only suppresses tumor growth but also stimulates systemic immune responses. This is evidenced by a reduction in M2-like and an increase in M1-like macrophages, enhanced dendritic cell (DC) maturation, and increased tumor infiltration of CD4⁺ and CD8⁺ T cells, accompanied by elevated IFN-γ secretion. This innovative use of ZrMOF/C@P offers a promising strategy to transform the immunosuppressive TIME, presenting a versatile and effective treatment option for solid tumors, and novel avenue for non-CDN-STING agonists, facilitating systemic administration.