One-stone-three-birds strategy: a graphdiyne oxide nanosheet-involved drug-formed immune-boosting hydrogel with dual responsivity for triple-modal cancer immunotherapy

Applying one-stone-three-birds strategy through nanotechnology and in situ delivery technology is beneficial to achieving triple-modal cancer immunotherapy. Herein, graphdiyne oxide nanosheet (GDYO), an emerging carbon nanomaterial, is applied as an immunostimulatory nanoplatform to construct JQ1-loaded GDYO nanocomposite (JQ1-GDYO) through π-π stacking interaction. Then, pH-thermo responsive drug-formed immune-boosting hydrogel (JQ1-GDYO@PM gel) is spontaneously fabricated after mixing JQ1-GDYO with the antineoplastic polymer polymetformin (PM) and the crosslinker dibenzaldehyde-functionalized PEG 2000 (DF-PEG) under physiological pH environment. Attributed to the outstanding self-healing performance, injectability, and pH-thermo sensitivity, precise local administration of this hydrogel can be easily achieved through a syringe. Meanwhile, the controlled release of PM, GDYO, and JQ1 is realized at tumor site upon 808 nm laser irradiation. Synergistically, these released drugs repolarize pro-tumoral macrophages to antitumoral phenotype. In addition, photothermal therapy (PTT)-induced local and systemic immune activation, and JQ1-mediated PD-L1 down-regulation exert a powerful immunotherapy effect against both primary and abscopal tumor, eventually facilitating the establishment of long-term immune memory to prevent tumor metastasis. Overall, this dual-responsive GDYO-involved immune-boosting hydrogel system shows great potential for triple-modal immunotherapy.