Circular Bivalent Aptamer Chimeras Leveraging LDLR-Mediated Lysosomal Shuttling for Targeted Protein Degradation.

Molecular design and delivery of extracellular and membrane protein degradation chimeras.

Extracellular and membrane-associated proteins constitute a substantial therapeutic target space that remains largely inaccessible to intracellular degradation strategies based on the ubiquitin-proteasome system. Membrane and extracellular targeted protein degradation (meTPD) addresses this limitation by coupling target recognition to degradation-competent uptake and intracellular sorting rather than relying on a single receptor or platform. In this Review, we organize meTPD strategies according to their trafficking and degradation routes, including lysosome-targeting receptor-dependent systems, transmembrane E3 ligase recruitment, receptor-independent internalization, lysosomal-sorting sequences and autophagy-mediated clearance. We then examine how ligand affinity and epitope accessibility, ternary-complex geometry, linker architecture, covalency, valency, receptor recycling and degrader reuse collectively determine productive degradation. Particular attention is given to spatial selectivity across tissues, cell populations and subcellular organelles, as well as to artificial intelligence-assisted design, stimuli-responsive activation and delivery systems that regulate the exposure and trafficking of meTPDs. Finally, we discuss emerging clinical evidence, convergence with antibody-drug conjugate-derived modalities, the hook effect and plausible resistance mechanisms. By integrating molecular design, receptor biology, intracellular trafficking, delivery and pharmacodynamic considerations, this Review provides a framework for selecting disease-matched degradation routes and advancing meTPDs from platform-specific demonstrations towards predictable therapeutic modalities.

Enzyme Activation of Triggerable Polymeric Lysosome Targeting Chimeras

Improving Proteolysis‐Targeting Chimera Delivery by Targeting Key Biomarkers in Tumor Endocytosis Pathways

Proteolysis‐targeting chimeras (PROTACs) are promising therapeutic agents for targeted protein degradation via the ubiquitin‐proteasome system; however, their clinical application is severely constrained by poor membrane permeability due to high molecular weight and polar surface area, limiting passive diffusion. Emerging evidence suggests that receptor‐mediated endocytosis within tumor microenvironments provides an alternative and potentially generalizable entry route for PROTAC delivery independent of classical diffusion. This review proposes a systematic framework for tumor endocytosis‐guided PROTAC delivery, centered on the identification and exploitation of endocytic biomarkers. A three‐tiered screening strategy is established based on tumor‐selective expression, validated internalization capacity, and functional relevance to tumor dependency. Using this framework, nine representative biomarkers are evaluated with respect to endocytic pathways, intracellular trafficking fate, and delivery suitability. Furthermore, we present a unified PROTAC engineering strategy matrix integrating ligand design, cleavable linker chemistry, and endosomal escape modules to align with receptor‐specific trafficking behaviors. A multiscale validation pipeline covering binding, internalization, intracellular release, and in vivo pharmacodynamics is also outlined. Collectively, this review establishes tumor endocytic pathways as programmable delivery interfaces, providing a rational roadmap for next‐generation PROTAC design with improved efficiency and translational potential.

Caged Glycan-Antibody Conjugates for Tumor-Selective Activation of Lysosome-Targeting Chimeras.

A chemically activatable LYTAC platform that leverages tumor microenvironment-specific cues to achieve precise and safe protein degradation in vivo is reported, significantly enhancing the safety and therapeutic window of lysosome-targeted degradation strategies in cancer therapy.

Expanding the Repertoire of Lysosomal Degradation of Membrane Proteins: A Generalizable Strategy Using Multivalent Antibody−Polymer Chimeras

Targeted protein degradation enables the removal of undesired proteins via proteasomal or lysosomal pathways without genomic alteration. Existing lysosomal strategies rely on chimeras that concurrently engage the protein of interest (POI) and a receptor that inherently directs bound proteins to the lysosome. We posit here that multivalent noncovalent interactions can trigger endosomal uptake and lysosomal degradation of specific membrane proteins in combination with an ancillary membrane protein, where the ancillary protein does not need to possess endogenous lysosome-directing characteristics. We demonstrate this relaxation of the ancillary protein characteristics using antibody–polymer conjugates, namely Polymeric Lysosome-Targeting Chimeras (PolyTACs), bearing ligands that polyvalently bind to membrane proteins. Using membrane carbonic anhydrase and PD-L1 as examples, we show the possibility of expanding the repertoire of lysosomal degradation of membrane POIs, which in turn opens up opportunities for new therapeutic possibilities.

TROP2-targeting chimeras (TRTACs) for tumor-selective membrane protein degradation and enhanced drug delivery

These findings establish TROP2 as a robust LTR and provide a versatile eTPD platform with profound translational potential for tumor treatment, as well as design TRTAC-drug conjugates, enabling targeted protein degradation together with enhanced drug delivery.