Tumor microenvironment-activated polypeptide nanoparticles for oncolytic immunotherapy

Area of Science:

• Biomaterials Science
• Cancer Immunotherapy
• Nanomedicine

Background:

• Cationic oncolytic polypeptides show promise for cancer treatment by directly lysing tumor cells and stimulating antitumor immunity.
• However, their clinical application is limited by poor tumor selectivity and systemic toxicity due to positive charges.

Purpose of the Study:

• To develop a tumor microenvironment-responsive nanoparticle (DNP) to enhance the safety and efficacy of cationic oncolytic polypeptides (PLP).
• To shield the positive charges of PLP and enable targeted release in acidic tumor conditions.

Main Methods:

• Self-assembly of a cationic oncolytic polypeptide (PLP) with a pH-sensitive anionic polypeptide to form DNPs.
• Evaluation of DNP stability at physiological pH (7.4) and release profile in acidic tumor microenvironment (pH 6.8).
• Assessment of DNP-induced immunogenic cell death, in vitro cytotoxicity, and in vivo antitumor efficacy, including inhibition of tumor growth, recurrence, and metastasis.

Main Results:

• DNPs effectively shielded the positive charges of PLP, enhancing biocompatibility and reducing inherent toxicity.
• DNPs remained stable at pH 7.4 but released PLP in the acidic tumor microenvironment (pH 6.8).
• DNPs induced potent immunogenic cell death and demonstrated significant in vivo inhibition of tumor growth, recurrence, and metastasis through direct oncolysis and immune activation.

Conclusions:

• pH-sensitive DNPs represent a promising strategy to improve the tumor selectivity and biosafety of cationic polypeptides for oncolytic immunotherapy.
• This nanoparticle system offers a potential platform for targeted delivery of oncolytic agents, enhancing therapeutic outcomes while minimizing side effects.