ApH-Responsive and Guanidinium-Rich NanoadjuvantEfficiently Delivers STING Agonist for Cancer Immunotherapy

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.