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

Enzyme Activation of Triggerable Polymeric Lysosome Targeting Chimeras

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.

Engineering Nonpathogenic Bacteria for Synergistic Tumor-Targeted Protein Degradation and Immunotherapy by Checkpoint-Inhibiting Nanobodies.

In vivo administration of engineered microbes led to marked tumor growth inhibition in both subcutaneous breast and orthotopic hepatocellular carcinoma models, along with prolonged animal survival, driven by remodeling of the suppressive tumor microenvironment through coordinated crosstalk between M1-like macrophages and tumor-resident memory (TRM)-like CD8+ T cells.

Development of Oncolytic Virus-Proteolysis-Targeting Chimera Conjugates for Tumor Immunotherapy.

In BPAD, the potent and highly selective infection of OVs to tumor cells enhances both cellular uptake and tumor-selective delivery of PROTACs, resulting in a 640-fold increase in the protein degradation efficiency.

Reprogramming PD-L1 endosomal recycling and lysosomal degradation via engineered exosome-based nanocomposites overcomes immune resistance in lung cancer brain metastasis

While anti-PD-L1 antibody (αPD-L1) therapy holds promise, its efficacy against lung cancer brain metastasis (LCBM) is severely limited by the blood-brain barrier (BBB), the immunosuppressive tumor microenvironment and adaptive immune resistance. To overcome these barriers, we engineered a pH-responsive nanocomposite (VP-αPD-L1@REB) by functionalizing brain-metastatic tumor cell-derived exosomes (EB) with RGD peptides (REB) for targeted co-delivery of verteporfin (VP) and αPD-L1. Benefiting from homotypic affinity and integrin-mediated transcytosis, VP-αPD-L1@REB efficiently crosses the BBB, accumulates within intracranial tumors, and undergoes pH-responsive cargo release. Mechanistically, VP induces a lethal reactive oxygen species (ROS) storm for direct tumor ablation. Simultaneously, VP downregulates the chaperone protein CMTM6 and activates cellular autophagy, forcibly driving internalized PD-L1 toward degradation via dual “endosome-lysosome” and “autophagy-lysosome” pathways. Driven by the synergy of VP's robust intracellular clearance and αPD-L1's surface blockade, this targeted nanoplatform successfully remodels the intracranial immunosuppressive microenvironment and triggers potent systemic anti-tumor immunity. This study provides a highly promising translational paradigm for overcoming adaptive immune resistance in central nervous system (CNS) malignancies.

Democratizing LYTACs-A Modular Click Chemistry Platform for the Rapid Assembly of Lysosome-Targeting Chimeras.

Lysosome-targeting chimeras (LYTACs) are emerging therapeutics that mediate extracellular targeted protein degradation. Through simultaneous engagement of a target protein of interest and a lysosomal trafficking receptor, these bifunctional molecules can facilitate the degradation of both secreted and cell-surface proteins. The original LYTACs were designed to engage the cation-independent mannose-6-phosphate receptor (CI-M6PR) via complex glycopolymer or glycopolypeptide ligands conjugated to target-specific antibodies. However, the complexity of these ligands has limited the broader adoption of LYTACs as research tools. Here, we describe a simple, rapid, and modular click chemistry platform for the generation of CI-M6PR-binding LYTACs. The approach utilizes only commercially available reagents and standard laboratory equipment and allows for the conversion of virtually any antibody into a LYTAC. This method for "democratizing" LYTAC generation should facilitate the widespread adoption of these tools for biological discovery.