CD44‐Assisted Transcytosable Chimeras for Extracellular Protein Depletion in Deep Tumors

Extracellular targeted protein degradation (eTPD) typically uses antibody-derived bifunctional chimeras to direct extracellular targets toward lysosomal degradation. However, the requirements for antibody modification complicate degrader design, and their large size hinders tissue penetration. While small-molecule degraders provide enhanced tissue permeability, they suffer from poor pharmacokinetics and a limited target scope. Here we develop CD44-Assisted Transcytosable CHimeras (CATCHs), a plug-and-play platform that leverages CD44-mediated transcytosis for extracellular protein depletion in deep tumors. CATCHs are built on a hyaluronan-containing nanoparticle chassis, functionalized with IgG-affinitive tags to recruit unmodified antibodies. This design enables rapid generation of CATCHs against diverse targets. We show that CATCHs can drive near-complete depletion of cell-surface proteins, including PD-L1 and HER2, within 3 h at single-digit nanomolar antibody concentrations. Mechanistic studies reveal that CATCHs remove target proteins in a CD44-dependent manner through not only lysosomal proteolysis but also transcytosis of protein targets into extracellular spaces. The transcytosis-inducing activity also allows CATCHs to penetrate deep tumor tissues via consecutive transcytosis and effectuate depletion in otherwise inaccessible regions. We show that PD-L1-targeting CATCHs could induce potent antitumor immunity by depleting PD-L1 throughout tumor tissues. This platform promises a versatile eTPD tool with implications for both biomedical research and therapeutic drug discovery.