GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE331nnn/GSE331406/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331406GEOGSEfalseTumor-targeted degradation of SIRPα reprograms tumor-associated macrophages and restores antitumor immunityTherapies 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.2026/05/26GSE331406GSM9745503GSM9745504GSM9745499GSM9745500GSM9745501GSM9745502GSM9745497GSM974549828330331406Mus musculus