Bioresponsive lysosome-targeting chimeras for targeted protein degradation
Lysosome-mediated degradation of extracellular proteins represents an emerging therapeutic paradigm that exploits cellular waste-disposal machinery to eliminate pathogenic targets. Despite its promise, achieving selective degradation of disease-associated proteins remains constrained by the scarcity of discovering highly effective disease-specific lysosome-targeting receptors. To address this limitation, we engineered NeuroTAC, a lysosome-targeting chimera (LYTAC) that bridges a sortilin-binding ligand-neurotensin (NT) to a disease-specific antibody targeting proteins overexpressed in tumors and inflammatory disorders. NeuroTAC demonstrated robust degradation efficacy against both membrane-bound and extracellular proteins in experimental models. Leveraging the dysregulated activity of matrix metalloproteinases (MMPs), a characteristic feature of tumor and inflammatory microenvironments, we further developed BioresTAC as an innovative bioresponsive LYTAC variant. This advanced construct integrates an MMP-cleavable linker and terminal RGD peptides, enabling MMP-triggered activation and spatial precision in MMP-enriched pathological niches. Systematic validation demonstrated that NeuroTAC and BioresTAC mediate broad-spectrum protein degradation with microenvironmental selectivity, enhancing therapeutic efficacy in cancer and psoriasis models. These findings advance the translational potential of lysosome-engaging biologics, offering a dual strategy for precision degradation through receptor recruitment and microenvironmental sensing. Overall design: RNA sequencing indicated the differences in the gene expression profiles of HepG2 cells treated with LYTAC and those untreated, with three duplicate samples in each group.