Protective NK Cell Reservoir Based on DNA Supramolecular Hydrogel for Enhanced Triple-Negative Breast Cancer Therapy

Adoptive natural killer (NK) cell therapy represents a promising strategy for triple-negative breast cancer, but its therapeutic efficacy is often limited by poor intratumoral persistence and functional exhaustion within the immunosuppressive tumor microenvironment. Here, we developed an injectable DNA supramolecular hydrogel-based NK cell delivery platform (NK@DSH) that functions as a protective reservoir for transferred NK cells. The DNA supramolecular hydrogel enabled efficient NK cell encapsulation under mild conditions while preserving both cell viability and functionality. In vivo fluorescence tracking demonstrated prolonged intratumoral persistence of NK cells for up to 7 d and increased NK cell accumulation within tumor tissues. In a 4T1 tumor-bearing mouse model, NK@DSH produced stronger tumor growth inhibition than free NK cell administration while showing negligible systemic toxicity. This DSH-based strategy provides a generalizable platform for adoptive cell therapy, offering new insights into overcoming cell-persistence barriers in the treatment of solid tumors.