A PD-L1-targeted and lactate-responsive DNA hydrogel enabling Mito-US therapy: dual functions for postsurgical cancer detection and eradication.

Abstract

The minimal residual disease (MRD) following tumor resection remains a major challenge for preventing recurrence. Existing treatments usually exhibit poor specificity for scattered tumor cells at the surgical site. Moreover, few strategies successfully combine real-time MRD monitoring with sustained therapeutic intervention, further limiting their efficacy. To address these issues, we developed a PD-L1-targeted and lactate-responsive DNA hydrogel (Gel@FX11-SPN_T). A key innovation lies in its dual-functional PD-L1 aptamers: they bind to PD-L1-positive tumor cells to facilitate in situ enrichment and block the PD-L1/PD-1 checkpoint to reactivate immunity. Structurally, the hydrogel network is crosslinked by lactate-responsive aptamers which are conjugated with fluorophore-quencher pairs. When exposed to lactate (a metabolite abundant in MRD microenvironment), the lactate-responsive aptamers undergo conformational changes which not only activates fluorescence for MRD monitoring but also triggers the hydrogel disassembly, allowing release of mitochondria-targeted FX11-SPN_T. Under ultrasound irradiation, FX11-SPN_T generates reactive oxygen species (ROS) and suppresses aerobic glycolysis, thereby inducing tumor cell apoptosis and immunogenic cell death, which was evidenced by the upregulation of calreticulin (CRT), high mobility group box 1 (HMGB1), and heat shock protein 70 (HSP70). This process promotes dendritic cell maturation and T-cell activation, thus establishing long-term immune memory that effectively eliminates residual tumor cells and inhibits metastasis.