Targeted polymeric nanoparticles enable epithelial translocation of PROTACs and preserve intracellular protein degradation activity

Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic modality for the degradation of disease-associated proteins. Despite their high therapeutic potential, their clinical translation is limited by poor membrane permeability and low oral bioavailability resulting from their beyond-rule-of-five physicochemical properties. Here, we report a targeted nanoparticle-based delivery strategy designed to facilitate intestinal permeation while preserving degradation efficiency in target cells. The CA19-9 antibody 121SLE was covalently coupled to the surface of PROTAC-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (hydrodynamic diameter <250 nm, encapsulation efficiency 68.6 ± 1.5%). While free compound did not exhibit detectable transepithelial transport, nanoparticle encapsulation enabled translocation across in vitro epithelial models, which was further enhanced two-fold by antibody-functionalization. Additionally, pharmacodynamic activity was preserved upon encapsulation, as demonstrated by efficient degradation of anaplastic lymphoma kinase (ALK) in target cells. Comparable levels of degradation were observed for free and nanoparticle-encapsulated PROTAC, confirming effective intracellular release and ternary complex formation. This synergistic approach addresses key challenges related to PROTAC cellular accumulation and epithelial transport, providing a translationally relevant strategy for further development towards nanocarrier-based oral delivery of PROTACs.