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Charge-reversible crosslinked nanoparticle for pro-apoptotic peptide delivery and synergistic photodynamic cancer therapy

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Abstract

Although anti-cancer nanotherapeutics have made breakthroughs, many remain clinically unsatisfactory due to limited delivery efficiency and complicated biological barriers. Here, we prepared charge-reversible crosslinked nanoparticles (PDC NPs) by supramolecular self-assembly of pro-apoptotic peptides and photosensitizers, followed by crosslinking the self-assemblies with polyethylene glycol to impart tumor microenvironment responsiveness and charge-reversibility. The resultant PDC NPs have a high drug loading of 68.3%, substantially exceeding that of 10%–15% in conventional drug delivery systems. PDC NPs can overcome the delivery hurdles to significantly improve the tumor accumulation and endocytosis of payloads by surface charge reversal and responsive crosslinking strategy. Pro-apoptotic peptides target the mitochondrial membranes and block the respiratory effect to reduce local oxygen consumption, which extensively augments oxygen-dependent photodynamic therapy (PDT). The photosensitizers around mitochondria increased along with the peptides, allowing PDT to work with pro-apoptotic peptides synergistically to induce tumor cell death by mitochondria-dependent apoptotic pathways. Our strategy would provide a valuable reference for improving the delivery efficiency of hydrophilic peptides and developing mitochondrial-targeting cancer therapies.

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Acknowledgements

The authors gratefully acknowledge the support from the National Natural Science Foundation of China (Nos. 82172084 and 81803002) and STI2030-Major Projects (No. 2022ZD0212500). Scheme is created with BioRender.com.

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Author notes

  1. Haijing Qu and Han Chen contributed equally to this work.

Authors and Affiliations

  1. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China

    Haijing Qu, Han Chen, Wei Cheng, Yuqing Pan, Zhiran Duan, Yanjun Wang & Xiangdong Xue

  2. National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China

    Haijing Qu, Han Chen, Wei Cheng, Yuqing Pan, Zhiran Duan & Xiangdong Xue

  3. Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China

    Yanjun Wang

  4. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China

    Xing-Jie Liang

Authors
  1. Haijing Qu
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  2. Han Chen
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  3. Wei Cheng
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  5. Zhiran Duan
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  6. Yanjun Wang
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  7. Xing-Jie Liang
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  8. Xiangdong Xue
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Corresponding authors

Correspondence to Xing-Jie Liang or Xiangdong Xue.

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Charge-reversible crosslinked nanoparticle for pro-apoptotic peptide delivery and synergistic photodynamic cancer therapy

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Qu, H., Chen, H., Cheng, W. et al. Charge-reversible crosslinked nanoparticle for pro-apoptotic peptide delivery and synergistic photodynamic cancer therapy. Nano Res. 16, 13267–13282 (2023). https://doi.org/10.1007/s12274-023-5912-7

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  • DOI: https://doi.org/10.1007/s12274-023-5912-7

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