2. Academic Validation
  3. A pH-Responsive and Guanidinium-Rich Nanoadjuvant Efficiently Delivers STING Agonist for Cancer Immunotherapy

A pH-Responsive and Guanidinium-Rich Nanoadjuvant Efficiently Delivers STING Agonist for Cancer Immunotherapy

  • ACS Nano. 2025 Feb 25;19(7):6758-6770. doi: 10.1021/acsnano.4c10202.
Xiao Lu 1,  Heming Xia 2 3,  Wei Gao 4,  Xingquan Pan 5,  Yue Yan 6,  Ran Zhang 7,  Yubin He 7,  Yiguang Wang 2 3,  Binlong Chen 2 3,  Dong Mei 1
Affiliations

Affiliations

  • 1 Clinical Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 3 Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems School of Pharmaceutical Sciences Peking University, Beijing 100191, China.
  • 4 Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas 77204-5037, United States.
  • 5 College of New Materials and Chemical Engineering, Beijing Institute of Petrochemical Technology, Beijing 102617, China.
  • 6 Department of Central Laboratory, Peking University First Hospital, Beijing 100034, China.
  • 7 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
PMID: 39933120 DOI: 10.1021/acsnano.4c10202
Abstract

As natural agonists of the stimulator of interferon genes (STING), cyclic dinucleotides (CDNs) have been identified as promising immunotherapies that trigger a potent immune response against tumors. However, the low stability, rapid clearance, inadequate cellular uptake, and inefficient cytosol localization heavily hinder the therapeutic efficacy of the hydrophilic and negatively charged 2', 3'-cyclic-GMP-AMP (cGAMP). How to efficiently deliver cGAMP into the endoplasmic reticulum (ER) to activate STING for immune priming remains challenging. Here, we report a pH-responsive and guanidinium-rich STING nanoagonist (nPGSA) for cytosol delivery of cGAMP. Compared with free cGAMP, nPGSA achieves up to a 37.4-fold enhancement of cellular internalization. The pH-sensitive and guanidinium-functional design facilitates quick release and endosome escape, thus enabling precise ER targeting of cGAMP and 33.9-fold amplification of STING sensibilization. Furthermore, through the modulation of tumor-associated macrophage (TAM) polarization, nPGSA elicits a potent antigen-specific cellular immune response and sustained tumor regression in melanoma- and neuroblastoma-bearing mice. Our study provides a promising strategy for the delivery of cGAMP, and it offers insights into the function of cGAMP in modulating the tumor immune microenvironment for Cancer Immunotherapy.

Keywords

STING; cancer immunotherapy; cyclic dinucleotides; nanoadjuvant; nanoparticle; ultra-pH-sensitive.

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