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.
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Authors Peng Zhang, Yaowei Zhu, Hailong Zhang, Shuai Tang, Guo Zf, Xuan Yi, Xiao Cj, X Chen
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Journal national science review
Year 2026
DOI
10.1093/nsr/nwag446
URL
https://doi.org/10.1093/nsr/nwag446
Keywords Keywords not found

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