Synthetic Chimeric Antigen Lysosome-Associated Receptor Redirects Targeted Protein to Degradation

Cells employ lysosomal degradation to eliminate extracellular and membrane proteins, which is a process that can be exploited for therapeutic purposes. Current lysosome-targeting chimeras (LYTACs) that hijack endogenous lysosome-associated receptors (LARs) to degrade pathogenic proteins are constrained by their reliance on endogenous receptor trafficking. Here we introduce synthetic chimeric antigen lysosome-associated receptors (CALARs) that reprogram cells to effectively sort extracellular proteins to lysosomes, operating independently of native ligand competition. Encoded within circular RNA, CALARs enable sustained suppression of immune checkpoints and growth factor receptors for over 1 week. This prolonged suppression enhances immune activation and substantially reduces the tumor burden in vivo. This study introduces a modular, genetically encodable platform for modulating protein expression and advancing cell-based therapeutics.