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Intracellular Delivery of Mitochondria-Targeting Cationic Polypeptides by pH-Responsive Nanoparticles to Induce

Renyong Yin1,2, Zhihui Guo1, Xueli Lv3

  • 1State Key Laboratory of Polymer Science and Technology, Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.

Biomacromolecules
|October 6, 2025
PubMed

Insights

pH-responsive nanoparticles (CA-NPs) improve the safety and tumor selectivity of mitochondria-targeting cationic polypeptides (MTPs). These nanoparticles induce targeted immunogenic cell death (ICD) for enhanced cancer immunotherapy.

Area of Science:

  • Biotechnology
  • Nanomedicine
  • Cancer Immunotherapy

Background:

  • Cationic polypeptides can induce immunogenic cell death (ICD) by targeting mitochondria.
  • Systemic application of cationic polypeptides is limited by poor tumor selectivity and toxicity.

Purpose of the Study:

  • To develop a pH-responsive nanoparticle (CA-NP) system to improve the delivery and safety of mitochondria-targeting polypeptides (MTPs).
  • To evaluate the efficacy of CA-NPs in inducing ICD and suppressing tumor growth.

Main Methods:

  • Electrostatic self-assembly of MTP and an acid-sensitive anionic polypeptide to form CA-NPs.
  • In vitro and in vivo studies to assess nanoparticle dissociation, MTP release, mitochondrial targeting, ICD induction, and tumor suppression.

Main Results:

  • CA-NPs effectively shielded MTP's positive charge, enhancing tumor accumulation and reducing systemic toxicity.
  • CA-NPs dissociated in acidic endolysosomes, releasing MTP for selective mitochondrial targeting.
  • MTP release induced mitochondrial dysfunction, reactive oxygen species generation, and ICD.
  • CA-NPs significantly suppressed tumor growth and activated systemic antitumor immunity.

Conclusions:

  • pH-responsive CA-NPs represent a promising platform for safe and precise cancer immunotherapy.
  • This nanoparticle system enhances MTP delivery, improves biosafety, and potentiates antitumor immune responses.

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