Ionizable Nano‐PROTAC Overcomes Endosomal Entrapment for Enhanced LRG1 Degradation and Tumor Suppression

Nanoscale proteolysis-targeting chimeras (nano-PROTACs) have emerged as a promising modality that circumvents conventional linker optimization using multivalent engineering. However, their therapeutic potential remains severely limited by inefficient cytosolic delivery caused by endosomal entrapment. To address this challenge, we integrated a tertiary-amine motif into amphiphilic conjugates, which co-assemble into nano-PROTACs (designed as i16-ET^NC) optimized for protein degradation. Mechanistically, i16-ET^NC exploits a synergistic dual mechanism in which the ionizable tertiary amine cooperates with a C16 hydrophobic tail to enhance cellular uptake and promote endosomal escape via proton sponge effects, enabling efficient delivery to the cytosol. This design achieves potent degradation of the oncogenic target leucine-rich α-2-glycoprotein 1 (LRG1) in 4T1 murine breast tumors. Systematic evaluation shows that i16-ET^NC effectively induces LRG1 degradation, leading to significant tumor growth inhibition, strong apoptosis induction, and notable tumor regression, all without detectable systemic toxicity. Overall, this study presents a broadly applicable strategy to address endosomal entrapment in targeted protein degradation, highlighting the therapeutic potential of nano-PROTACs.