Programmable DNA hydrogels for dual-mode PD-L1 suppression via polyvalent LYTAC mimics and transcriptional silencing

Area of Science:

• Biomaterials Science
• Cancer Immunology
• Molecular Oncology

Background:

• Immune checkpoint blockade therapy shows promise in oncology but faces challenges with low response rates and acquired resistance, often due to insufficient Programmed death-ligand 1 (PD-L1) suppression.
• Traditional antibodies have limitations, and targeting intracellular and transcriptional drivers of checkpoint expression remains difficult.
• Proteolysis-targeting chimeras offer an alternative but require effective strategies for comprehensive PD-L1 modulation.

Purpose of the Study:

• To develop a programmable, tumor-responsive DNA hydrogel platform for dual-mode modulation of PD-L1.
• To investigate a synergistic "degrade-and-silence" approach for dismantling PD-1/PD-L1-mediated immunosuppression.
• To enhance the efficacy of cancer immunotherapy by addressing PD-L1 resistance mechanisms.

Main Methods:

• Synthesis of a DNA hydrogel platform using rolling circle amplification.
• Co-delivery of aptamer-based lysosome-targeting chimeras (LYTAC mimics) for extracellular PD-L1 degradation.
• Delivery of siSMARCAL1 to silence transcriptional activation of PD-L1, coupled with localized, sequential release within the tumor microenvironment.

Main Results:

• The DNA hydrogel platform achieved synergistic "degrade-and-silence" modulation of PD-L1.
• Effective dismantling of PD-1/PD-L1-mediated immunosuppression and triggering of immunogenic cell death.
• Significant suppression of primary tumor growth and prevention of postoperative recurrence in murine melanoma models, eliciting a robust systemic antitumor immune response.

Conclusions:

• The developed DNA hydrogel represents a versatile, programmable strategy for protein degradation and multilevel checkpoint modulation.
• This approach offers a generalizable method for enhancing cancer immunotherapy efficacy by overcoming PD-L1-mediated resistance.
• The findings highlight the potential of DNA-based materials in advancing precision cancer treatment.