Optogenetics-based synthetic biology holds great promise as a cell-based therapy strategy for many clinical incurable diseases; however, precise control over genetic expression strength and timing through disease state-related closed-loop regulation remains a challenge due to the lack of reversible probes to indicate real-time metabolite fluctuations. Here, based on a novel mechanism of analyte-induced hydrophobicity regulation of energy acceptors confined in mesoporous silica, we developed a smart hydrogel platform comprising glucose reversible responsive upconversion nanoprobes and optogenetic engineered cells, in which the upconverted blue light strength was adaptively tuned through blood glucose levels to control optogenetic expressions for insulin secretion. The intelligent hydrogel system enabled convenient maintenance of glycemic homeostasis through simple near-infrared illuminations without any additional glucose concentration monitoring, which efficiently avoided genetic overexpression-induced hypoglycemia. This proof-of-concept strategy efficiently combines diagnostics with optogenetics-based synthetic biology for mellitus therapy, opening up a new avenue for nano-optogenetics.