Modular Nanoassemblies Mimicking p62 Aggregates for Targeted Organelle Sequestration and Degradation against Breast Cancer

Selective autophagy relies on multivalent recognition by receptors like SQSTM1/p62 to form aggregates that cluster disperse organelles, undergoing liquid–liquid phase separation to facilitate their clearance and maintain cellular homeostasis. Inspired by this, we present the multivalent nanoparticle-based organelle targeting chimera (NanoTACOrg) to efficiently degrade organelles by flexibly clustering organelles for sequestration and facilitating targeted recruitment of autophagosomes. NanoTACOrg, assembled with a PLGA core, lysosomal escape modules, organelle-targeting modules, and LC3B binding modules, is programmed to selectively degrade various organelles, including mitochondria, endoplasmic reticulum, and Golgi apparatus. After endocytosis and lysosomal escape, NanoTACOrg targets subcellular compartments and mimics p62 aggregate-driven organelle clustering and degradation, without exhibiting the “hook effect”. Specifically, NanoTACMito-mediated mitochondrial degradation disrupts oxidative phosphorylation (OXPHOS) while enhancing compensatory glycolysis, thus sensitizing tumor cells to the glucose transporter 1 (GLUT1) inhibitor BAY-876. BAY-876 loaded NanoTACMito potently inhibits tumor growth, recurrence, and metastasis, demonstrating superior therapeutic efficacy by simultaneously targeting OXPHOS and glycolysis. These findings highlight the potential of NanoTACOrg as a versatile and effective platform for cancer therapy, particularly through organelle-specific degradation and metabolic reprogramming.