Stepwise-coordinated polymeric nanoplatform enables traceless cytosolic protein delivery and autophagy blockade for enhanced tumor therapy

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ID: 321653
2026
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Abstract
Abstract Autophagic degradation of proteins following cellular internalization and endosomal escape presents a significant, yet underexplored, challenge in intracellular protein delivery. This highlights the need for delivery carriers capable of concurrently achieving cytosolic delivery and autophagy inhibition. Here, we report a stepwise-coordinated polymeric nanoplatform based on a tailor-made amphiphilic triblock copolymer (mPEG-b-PGBA-b-PGCQ) that enables traceless cytosolic delivery of functional proteins while concurrently suppressing autophagy. This system incorporates three modular blocks: an mPEG stealth shell, a PGBA block for reversible protein conjugation via pH-sensitive iminoboronates, and a PGCQ block grafted with autophagy inhibitor hydroxychloroquine (HCQ) via self-immolative disulfide linkages. Using ribonuclease A (RNase A) as a model therapeutic, we demonstrated efficient protein release in acidic endolysosomes, simultaneous HCQ-promoted endosomal escape, and glutathione-triggered HCQ liberation in cytosol. The released HCQ significantly enhanced RNase A-induced apoptosis by inhibiting both the autophagic degradation of the protein and RNase A-induced mitophagy. Furthermore, by integrating cytosolic delivery with autophagy inhibition, this platform produced notable functional enhancement across multiple proteins, including green fluorescent protein, β-galactosidase, and horseradish peroxidase, demonstrating its broad utility. Our work establishes a potent traceless delivery and autophagy-blockade strategy for boosting intracellular protein efficacy, with considerable potential in both basic research and biomedical applications.
Reference Key
openalex_W7169784317 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Peng Zhang, Yaowei Zhu, Hailong Zhang, Shuai Tang, Guo Zf, Xuan Yi, Xiao Cj, X Chen
Journal national science review
Year 2026
DOI
10.1093/nsr/nwag446
URL
https://doi.org/10.1093/nsr/nwag446
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