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

Abstract

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.

A Near-Infrared-II Fluorescent Nanocatalyst for Enhanced CAR T Cell Therapy against Solid Tumor by Immune Reprogramming

“…This is attributed to the regulation of glycolytic metabolism in tumor cells, which reversed the tumor immunosuppressive microenvironment and undoubtedly gave CAR T cells a more favorable living space. Notably, immunomodulatory CD4 + T cells and cytotoxic CD8 + T cells are two characteristic manifestations of CAR T cell activation and differentiation and also the main effectors that trigger the body’s antitumor immune response . As shown in Figure b,c, synergistic therapy (APHA@CM+US+NIR), as a way to drive ICD in tumor cells, promoted the differentiation of CD4 + /CD8 + CAR T cells more pronouncedly than APHA@CM alone, causing stronger T cell activation.…”

“…Notably, immunomodulatory CD4 + T cells and cytotoxic CD8 + T cells are two characteristic manifestations of CAR T cell activation and differentiation and also the main effectors that trigger the body's antitumor immune response. 46 As shown in Figure 6b,c, synergistic therapy (APHA@CM+US+NIR), as a way to drive ICD in tumor cells, promoted the differentiation of CD4 + /CD8 + CAR T cells more pronouncedly than APHA@CM alone, causing stronger T cell activation. Notably, the activated CAR T cells induced large-scale outbreaks of granzyme B, perforin, and IFN-γ (Figure 6d−f), which were an effective weapon to kill tumor cells and accelerate the death process of tumor cells.…”

“…Notably, the activated CAR T cells induced large-scale outbreaks of granzyme B, perforin, and IFN-γ (Figure 6d−f), which were an effective weapon to kill tumor cells and accelerate the death process of tumor cells. 38,46 Surprisingly, the synergistic therapy even extended the survival time of CAR T cells in the TME, which was manifested by a significant increase in antiapoptotic protein (BCL-xL) on the CAR T cells after treatment in the APHA@CM+US+NIR group compared to the Control group (Figure 6g). 47 This exciting result motivates us to explore the induction of antitumor immunotherapy capabilities under combination therapy in vivo.…”

Protocatechuic Acid-Based Supramolecular Hydrogel Targets SerpinB9 to Achieve Local Chemotherapy for OSCC

“…Considering these issues, we aimed to seek an inexpensive and efficient matter that targets certain oncoproteins and could be integrated into our dual-functional hydrogel. In this study, to establish a stable system, we selected potassium as the core of PCA due to its proper diameter, which was suitable to act as the core of the isoG quartet, − and we observed that PCA and isoG could form a stable and injectable hydrogel following several simple steps. This modality was endowed with targeted bioactivity due to the involvement of PCA.…”

“…Based on the above presumption, we initially investigated the expression and biological function of Sb9 in OSCC. After confirming that cancer cell death could be triggered by inhibiting Sb9 expression, we designed and constructed the isoguanosine (isoG)-phenylenebisboronic acid (PBA)-PCA supramolecular hydrogel (PCA gel) by introducing a dynamic covalent borate ester bond using simple procedures in the presence of potassium, which was the most suitable core of the isoG-related hydrogel due to its proper diameter according to previous works. − This is the first time a local delivery system has been reported for PCA. Various experimental techniques were used to confirm the structure and properties of the PCA gel.…”