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Published on: November 9, 2020
Engineered Lysosome-Targeted Protein Degradation via Hijacking Macropinocytosis
Wen Xu1, Henggong Pan1, Yalan Han1
1College of Food Science and Technology, Yunnan Agricultural University, No. 452 Fengyuan Road, Kunming 650000, China.
ACS Nano
|June 17, 2026
Summary
Macropinocytosis-Targeting Chimeras (MapTACs) offer a novel approach for targeted protein degradation of extracellular proteins. This platform bypasses receptor dependency, enabling broad applications in various diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Targeted protein degradation (TPD) is a powerful tool for degrading intracellular proteins.
- Current TPD methods struggle with extracellular targets, requiring complex, case-specific designs.
- Extracellular protein degradation is challenging due to reliance on receptor-mediated endocytosis.
Purpose of the Study:
- To develop a novel TPD platform for efficient extracellular protein degradation.
- To introduce Macropinocytosis-Targeting Chimeras (MapTACs) as a universal TPD solution.
- To overcome limitations of receptor-dependent TPD strategies.
Main Methods:
- MapTACs utilize macropinocytosis, a receptor-independent pathway, for protein delivery to lysosomes.
- Dextran scaffolds are conjugated with aptamers or antibodies to target specific extracellular proteins.
- Degradation efficiency is assessed via time- and dose-dependent assays and macropinocytosis dependence.
Main Results:
- MapTACs effectively degrade monocyte chemotactic protein-1 (MCP-1) in a macropinocytosis-dependent manner.
- The platform demonstrates broad applicability across various cell types and targets like TNF-α and IFN-γ.
- In vivo studies show MapTACs reduce TNF-α levels in an acute inflammation model, attenuating lung injury.
Conclusions:
- MapTACs provide a universal, cost-effective, and scalable platform for extracellular protein degradation.
- This approach overcomes receptor-specific limitations of existing TPD tools.
- MapTACs open new therapeutic avenues for diseases involving extracellular protein dysregulation, including cancer and inflammation.
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