Targeted Lipid–Polymer Nanoparticles Enable Gene‐Encoded TRIM21 Degraders for Programmable Protein Degradation

ABSTRACT Precise and reversible control of endogenous protein abundance in vivo remains a formidable challenge, particularly for targets refractory to small‐molecule or traditional genetic perturbation. Here, we report a gene‐encoded, programmable protein‐degradation nanoplatform enabled by targeted lipid–polymer hybrid nanoparticles. Through the systematic engineering of poly(β‐amino ester) nanocarriers and their integration with cationic lipids and a transferrin‐receptor targeting ligand, we achieve highly efficient cytosolic delivery of plasmids encoding degradation‐competent E3‐ligase fusion proteins. These plasmid payloads drive the intracellular expression of programmable degraders, triggering the ubiquitin–proteasome‐mediated elimination of endogenous proteins without requiring modification of endogenous target genes or direct delivery of preformed antibodies or recombinant proteins. Based on the findings, this nanoplatform supports the selective depletion of diverse protein classes, including cytosolic enzymes, membrane‐associated immune checkpoints, and aggregation‐prone neuronal proteins, yielding high on‐target potency with minimal off‐target transcriptional perturbation. Crucially, systemic administration yielded proof‐of‐concept tumor‐ and brain‐targeted gene delivery, target‐protein depletion in preclinical models, and encouraging therapeutic signals in selected cancer and neurodegeneration models. By unifying advanced nanomaterial engineering with gene‐encoded degradation, this study addresses key in vivo delivery challenges of conventional Trim‐Away technology, establishing a highly adaptable blueprint for next‐generation protein‐degradation therapeutics.