ABSTRACT Targeting the CD47–SIRPα axis holds substantial therapeutic promise, however, its clinical translation has been hampered by dose‐limiting hematotoxicity and poor intratumoral delivery of therapeutics. Here, we describe an integrated bioengineering platform that simultaneously resolves both challenges. We engineered a biomimetic SIRPα‐based Chimeric Antigen Receptor (CAR) that operates via an avidity‐driven mechanism, enabling it to functionally discriminate the high‐density CD47 presentation on tumor cells from the low‐density distribution on erythrocytes. When delivered intratumorally as mRNA via peptide‐functionalized lipid nanoparticles (LNPs), this system achieves selective, spatially confined reprogramming of tumor‐associated macrophages (CAR‐TAMs). Mechanistically, this reprogramming is profound, underpinned by a STAT1/IRF1‐driven transcriptomic shift and a metabolic switch to aerobic glycolysis. Functionally, this transforms TAMs into dual‐action effectors that not only mediate direct phagocytosis but also orchestrate a robust CD8⁺ T‐cell influx, converting the tumor from immunologically “cold” to “hot”. In a syngeneic solid tumor model expressing human CD47, this resulted in marked tumor regression and prolonged survival, while safety evaluation revealed no treatment‐related hematological or systemic toxicity. This work establishes a safe and translatable blueprint for in situ cell immunotherapy, providing an integrated solution to the foundational roadblocks of targeting ubiquitously expressed antigens.
Zhang et al. (Sun,) studied this question.