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

ABSTRACT 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.