CD44-Assisted Transcytosable Chimeras for Extracellular Protein Depletion in Deep Tumors.

Area of Science:

• Biochemistry
• Molecular Biology
• Nanotechnology

Background:

• Extracellular targeted protein degradation (eTPD) traditionally relies on antibody-derived chimeras, which face challenges in design complexity and tissue penetration.
• Small-molecule degraders offer better permeability but have limitations in pharmacokinetics and target range.

Purpose of the Study:

• To develop a novel platform, CD44-Assisted Transcytosable CHimeras (CATCHs), for efficient extracellular protein depletion in deep tumors.
• To leverage CD44-mediated transcytosis for enhanced delivery and degradation of extracellular targets.

Main Methods:

• Designed CATCHs using a hyaluronan-based nanoparticle chassis functionalized with IgG-binding tags to recruit unmodified antibodies.
• Utilized CD44-mediated transcytosis for nanoparticle and protein target translocation across tissues.
• Assessed protein depletion efficacy (e.g., PD-L1, HER2) and tumor penetration in preclinical models.

Main Results:

• CATCHs achieved near-complete depletion of cell-surface proteins within 3 hours at low antibody concentrations.
• Demonstrated CD44-dependent degradation via lysosomal proteolysis and transcytosis of protein targets.
• Showcased deep tumor penetration and depletion in inaccessible regions through consecutive transcytosis.
• PD-L1-targeting CATCHs induced significant antitumor immunity.

Conclusions:

• CATCHs represent a versatile, plug-and-play platform for extracellular targeted protein degradation with improved tissue penetration.
• The platform enables efficient depletion of extracellular targets in deep tumors, offering a promising approach for cancer therapy and research.