PROteolysis TArgeting Chimeras (PROTACs) enable event-driven therapy by eliminating oncogenic proteins via the ubiquitin–proteasome system. Yet systemic application in solid tumors is often limited by high molecular weight, poor aqueous solubility, suboptimal pharmacokinetics, and off-target liabilities. Here we develop a blood-stable, tumor-activatable PROTAC nanoformulation and test it in orthotopic glioblastoma and pancreatic cancer models.

pH-responsive, crosslinked polymeric nanoparticles were engineered from PEG–PBLA and pH-labile linkers by self-assembly followed by post-assembly crosslinking. A panel of PROTACs (ARV825, LC2, ARV471, QC-01-175 and others) was screened, and formulations were optimized using particle size/dispersity, serum stability, and encapsulation efficiency. pH-dependent destabilization/release was evaluated under mildly acidic conditions relevant to the tumor microenvironment and endo/lysosomes. In vitro activity was assessed in glioblastoma cells (ARV825) and pancreatic cancer cells (LC2) using viability assays together with pharmacodynamic readouts consistent with PROTAC action. In vivo efficacy and tolerability were examined after intravenous dosing in orthotopic GL-261-luc glioblastoma and orthotopic MIA PaCa-2-luc pancreatic cancer models using longitudinal bioluminescence imaging, survival analyses, and liver/kidney toxicity markers.

Linker and formulation optimization enabled robust PROTAC nanoparticles that remained stable in serum while becoming labile under acidic conditions. Hydrophobic payloads (approximately logP > −1) were broadly encapsulated, whereas a highly water-soluble PROTAC (lenalidomide) loaded poorly, defining a practical encapsulation boundary for this platform. Compared with free PROTACs, optimized nanoparticles improved blood retention and tumor accumulation, enhanced antitumor activity in vitro and in vivo, and attenuated liver/kidney toxicity signals. Both orthotopic models showed significant tumor growth suppression and a significant survival benefit versus controls.

pH-responsive crosslinked nanoparticles can convert PROTACs into systemically deliverable therapeutics with improved efficacy and safety signals in hard-to-treat solid cancers. This platform provides actionable design rules (payload physicochemical window and linker/formulation tuning) to accelerate translational targeted protein degradation therapy.

This research was supported financially by the Research on Development of New Drugs (23ak0101173) from Japan Agency for Medical Research and Development (AMED). We welcome collaborations using our PROTAC-encapsulating nanoparticle platform.(kinoh-h (at mark) kawasaki-net.ne.jp)