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A Cascade-Targeted Enzyme-Instructed Peptide Self-Assembly Strategy for Cancer Immunotherapy through Boosting

Limin Xie1,2, Yinghao Ding2, Xiangyang Zhang2

  • 1State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, 300071, P. R. China.

Small Methods
|March 25, 2023
PubMed

Insights

This study introduces a novel peptide nanomedicine, Compound 4, designed to induce immunogenic cell death (ICD) in cancer. It effectively targets mitochondria and triggers an immune response, inhibiting tumor growth by leveraging mitochondrial dysfunction and immune system activation.

Area of Science:

  • Biomedical Engineering
  • Nanomedicine
  • Cancer Therapy

Background:

  • Immunogenic cell death (ICD) shows promise for cancer treatment by targeting mitochondrial functions, but strategies are still developing.
  • Developing targeted nanomedicines is crucial for effective cancer therapy.

Purpose of the Study:

  • To construct a multifunctional peptide nanomedicine (Comp. 4) for ICD-based cancer therapy.
  • To investigate the targeting, assembly, and therapeutic efficacy of Comp. 4 in a cancer model.

Main Methods:

  • Designed a peptide nanomedicine (Comp. 4) incorporating lonidamine (LND), a PD-L1 binding peptide, a mitochondria-targeting motif (TPP), and an enzyme-responsive assembly core.
  • Evaluated Comp. 4's response to alkaline phosphatase (ALP) and its assembly within cancer cells (CT26).
  • Assessed Comp. 4's ability to induce mitochondrial oxidative stress, ICD, and antitumor immunity in vivo.

Main Results:

  • Comp. 4 demonstrated structural changes in the presence of ALP and formed peptide assemblies in CT26 cells.
  • The nanomedicine facilitated endocytosis, endosomal escape, and LND delivery to mitochondria.
  • Comp. 4 effectively induced mitochondrial oxidative stress, robust ICD, and inhibited tumor growth by eliciting systemic antitumor immunity.

Conclusions:

  • The developed peptide nanomedicine (Comp. 4) shows significant potential for cancer therapy by inducing ICD and stimulating antitumor immunity.
  • Targeted delivery and enzyme-instructed self-assembly are effective strategies for enhancing nanomedicine efficacy in cancer treatment.
Keywords:
cascade-targeted capacitiesenzyme-instructed peptide self-assembly (EISA)immunogenic cell death (ICD)mitochondriaprogrammed death ligand 1 (PD-L1)

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