An Engineered Nanovesicles-Based Lysosome-Targeting Protein Degradation Platform (NV-TACs) for Cancer Immunotherapy

Area of Science:

• Biotechnology
• Molecular Biology
• Cancer Research

Background:

• Lysosome-Targeting Chimeras (LYTAC) enable targeted degradation of extracellular and membrane proteins.
• Current LYTAC technologies face challenges in ligand screening, linker optimization, and balancing protein characteristics.

Purpose of the Study:

• To develop a novel, linker-free LYTAC platform named NV-TACs (Nanovesicle-based Targeting Chimeras).
• To overcome limitations of existing LYTAC systems through bioinspired, modular design.

Main Methods:

• Engineered fibroblast-derived nanovesicles displaying endogenous ligands for protein of interest (POI) and lysosome-targeting receptors (LTRs).
• Integrated PD-1 (for PD-L1) and transferrin (for transferrin receptor, TFRC) into nanovesicles.
• Incorporated therapeutic payload ML210 for combined protein degradation and ferroptosis.

Main Results:

• NV-TACs demonstrated efficient degradation of PD-L1 on tumor and immune cells via TFRC-mediated endocytosis.
• The platform showed scalability and modularity for degrading various membrane proteins.
• NV-TACs achieved simultaneous targeted protein degradation and ML210-mediated ferroptosis.
• Significant therapeutic efficacy was observed in both anti-PD-1-responsive and -resistant tumor models with minimal toxicity.

Conclusions:

• NV-TACs represent a scalable, modular, and bioinspired platform for targeted protein degradation.
• This linker-free approach overcomes key challenges in LYTAC technology.
• NV-TACs show potential for novel cancer therapeutics combining protein degradation and targeted cell death induction.