Tumor-targeted degradation of SIRPα reprograms tumor-associated macrophages and restores antitumor immunity

Therapies targeting the CD47–SIRPα "don't eat me" axis are currently hampered by limited tissue penetration and dose-limiting hematotoxicity. Here, we report a tumor-targeted mRNA nanotherapeutic that selectively degrades SIRPα on macrophages to unleash antitumor immunity in colorectal cancer. We formulated mRNA encoding an Fc-fused SIRPα degrader into VEGFR2-targeted lipid nanoparticles (LNPs) to achieve tumor-specific delivery. This system triggers lysosomal degradation of SIRPα, repolarizing tumor-associated macrophages toward a pro-inflammatory, phagocytic state that drives CD8⁺ T cell priming. In contrast to the hematologic toxicity associated with systemic CD47 blockade, this strategy demonstrated superior tumor control in syngeneic and orthotopic CRC models while preserving a normal hematologic profile. Single-cell transcriptomics confirmed the remodeling of the immunosuppressive myeloid landscape. These findings establish targeted SIRPα degradation as a potent, safe alternative to systemic CD47 blockade, offering a versatile platform to reprogram myeloid checkpoints in solid tumors.