Thermosensitive Hydrogel Sustaining the Release of Lymph-Draining Oligonucleotide Adjuvant Polyplex Micelles Improves Systemic Cancer Immunotherapy.

Immune checkpoint blockade (ICB) immunotherapies are a powerful tool in the clinical management of cancer, but response rates to ICB remain limited, and treatment-related toxicities can be significant. Therapeutic efficacy of ICB can be enhanced by delivering synergistic immunomodulators to tumor-draining lymph nodes (TdLNs). However, achieving sustained release of small molecule immunomodulators into the lymphatics and TdLNs remains challenging. To address this limitation, a sustained release system for delivering an oligonucleotide adjuvant to lymph nodes (LNs) was developed. CpG oligonucleotide was complexed with a redox-responsive cationic polymer and mixed with F127-g-Gelatin to generate a thermosensitive hydrogel that releases lymph-draining polyplex micelles in situ. This CpG/BPEI-SS-/F127-g-Gelatin (CpG-HG) system enhanced the quantity and duration of CpG delivery to TdLNs following locoregional administration compared with free drug and enabled targeted, potent, and prolonged immunomodulation within TdLNs from a single administration. This augmented, localized immune response synergized with systemic ICB treatment, both markedly amplifying the systemic circulating CD8+ T cell response and improving antitumor therapeutic efficacy while enabling ICB dose reduction. These results highlight the potential for this drug delivery system as an adjunct to existing clinical ICB protocols to improve patient outcomes.