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

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Minimal residual disease (MRD) after tumor resection is a key factor in cancer recurrence.
• Current treatments lack specificity for scattered tumor cells and fail to integrate real-time monitoring with therapy.
• Effective strategies for detecting and treating MRD are crucial for improving patient outcomes.

Purpose of the Study:

• To develop a dual-functional DNA hydrogel for targeted therapy and real-time monitoring of minimal residual disease (MRD).
• To investigate the hydrogel's ability to block the PD-1/PD-L1 checkpoint and reactivate anti-tumor immunity.
• To assess the hydrogel's efficacy in inducing tumor cell apoptosis and long-term immune memory.

Main Methods:

• Development of a PD-L1-targeted and lactate-responsive DNA hydrogel (Gel@FX11-SPN_T).
• Utilizing dual-functional PD-L1 aptamers for tumor cell enrichment and immune checkpoint blockade.
• Employing lactate-responsive aptamers for fluorescence-based MRD monitoring and drug release upon ultrasound irradiation.
• Assessing the release of mitochondria-targeted FX11-SPN_T to induce reactive oxygen species (ROS) and suppress glycolysis.

Main Results:

• The hydrogel successfully targets PD-L1-positive tumor cells and blocks the PD-1/PD-1 checkpoint.
• Lactate triggers hydrogel disassembly, activating fluorescence for MRD monitoring and releasing the therapeutic agent.
• Ultrasound-activated FX11-SPN_T induces tumor cell apoptosis via ROS generation and glycolysis suppression, evidenced by CRT, HMGB1, and HSP70 upregulation.
• The treatment promotes dendritic cell maturation and T-cell activation, establishing immune memory against residual tumor cells and metastasis.

Conclusions:

• The developed DNA hydrogel offers a promising strategy for real-time MRD monitoring and targeted cancer therapy.
• This approach effectively eliminates residual tumor cells by reactivating anti-tumor immunity and inducing immunogenic cell death.
• The combination of in situ monitoring and sustained therapeutic intervention holds potential for preventing cancer recurrence and metastasis.