Transforming cold tumors into hot ones via tumor-microenvironment-responsive siRNA micelleplexes for enhanced immunotherapy

It is highly desirable to turn cold tumors into hot ones to improve the efficacy of antitumor immunotherapy. Herein, we develop the peptide-based small interfering RNA (siRNA) micelle-plexes (P-A7R@siPD-L1) for normalizing vascular-immune crosstalk to establish a positive feedback loop in potentiating antitumor immunotherapy. These micelleplexes are equipped with tumor-microenvironment-responsive property for precise drug delivery and release. The prepared P-A7R@siPD-L1-mediated photodynamic therapy could eliminate solid tumors and trigger immunogenic cell death to generate systematic immune responses. Meanwhile, the antiangiogenic peptide A7R normalizes the tumor vasculature by converting chaotic vascular systems into matured and organized ones, thus alleviating tumor hypoxia and promoting intratumoral infiltration by immune cells. Antitumor immunogenicity would be further strengthened with the aid of siPD-L1 by muting the resistance of tumor cells against immune effector cells. This study pro-vides a unique therapeutic strategy in turning cold tumors into hot tumors enabled by siRNA nanomaterial.

Automated summary

In this study, peptide-based siRNA nanomaterials were developed to enhance the efficacy of antitumor immunotherapy. These nanomaterials respond to the tumor microenvironment and enable precise drug delivery and release. Photodynamic therapy mediated by these nanomaterials can eliminate solid tumors and induce immunogenic cell death, generating systemic immune responses. Additionally, the normalization of tumor vasculature and the silencing of tumor cells' resistance to immune effector cells further strengthen the antitumor immunogenicity.