Abstract Background Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) typically polarize toward an M2 phenotype that promotes tumor progression and immune suppression. Reprogramming TAMs to the proinflammatory M1 phenotype has emerged as a promising strategy to boost antitumor immunity. This study aimed to develop a targeted nanoplatform to deliver small activating RNAs (saRNAs) that upregulate genes involved in macrophage reprogramming. Results We designed saRNAs targeting the promoters of p38 and TFEB, encapsulated within a metal-organic framework (MOF)-based delivery system and cloaked with hybrid membranes composed of synthetic lipids and exosome-derived vesicles. These were further functionalized with the TAM-targeting peptide CRV (CRVLRSGSC), resulting in nanoparticles termed CLMSR. CLMSR selectively accumulated in macrophages, enhancing intracellular saRNA delivery. Functional assays revealed that conditioned medium from CLMSR-treated M2 macrophages suppressed tumor cell migration, invasion, and 3D spheroid formation. In vivo, CLMSR demonstrated prolonged circulation time and enhanced tumor targeting. Importantly, treatment remodeled the TME by increasing CD8⁺ and CD4⁺ T cell infiltration and promoting TAM repolarization from the M2 to M1 phenotype. Conclusions Our findings demonstrate that CLMSR represents a novel and efficient nanoplatform for saRNA delivery to reprogram TAMs and modulate the TME. By targeting M2 macrophages and inducing their transition to the tumoricidal M1 phenotype, this approach offers a promising therapeutic avenue to enhance antitumor immunity and inhibit tumor progression. Graphical abstract
Yu et al. (Thu,) studied this question.