Inosine-Based Supramolecular Hydrogel for Highly Efficient PD-L1 Blockade Therapy via Mediating CD8+ T Cells

Inosine is proven to promote the proliferation and function of CD8(+) cytotoxic lymphocytes (CD8(+) T) under glucose restriction and enhance the efficacy of programmed cell death protein ligand-1 (PD-L1) blockade therapy. However, systemic administration of high frequencies and large doses of inosine and anti-PD-L1 antibody (aPDL1) is required, which inevitably reduces bioavailability and causes severe immunological side effects. Therefore, it is crucial to develop a drug delivery system to achieve gradient release of inosine and aPDL1 for local immunotherapy. In this study, an inosine-based supramolecular hydrogel, inosine-phenylenediboronic-isoguanosine (IPBisoG), is successfully developed following a simple one-pot procedure. Both in vitro and in vivo studies demonstrate that the biocompatible and biodegradable IPBisoG hydrogel displays excellent stability and self-healing properties. Furthermore, the IPBisoG hydrogel is shown to achieve the gradual and sequential release of inosine and aPDL1. Inosine, which enhances the proliferation and function of CD8(+) T cells, together with aPDL1, the blocker of the immunosuppressive pathway in tumor microenvironment, can highly enhance the in vivo efficacy of PD-L1 blockade therapy. The employment of IPBisoG hydrogel is also shown to trigger systemic immune responses. These results demonstrate that IPBisoG hydrogel can be a promising platform for tumor-local immunotherapy in the future.

Automated summary

A supramolecular hydrogel called inosine-phenylenediboronic-isoguanosine (IPBisoG) has been successfully developed, which demonstrates excellent stability and self-healing properties. The hydrogel can achieve gradual and sequential release of inosine and PD-L1 blocker, enhancing the efficacy of local immunotherapy. The use of the hydrogel also triggers systemic immune responses.