Supramolecular mRNA-delivering hydrogel for inducing tertiary lymphoid structures and enhancing immunotherapy efficacy

Immune checkpoint blockade has improved cancer treatment outcomes, yet many solid tumors remain immunologically “cold” and resistant to therapy. Tertiary lymphoid structures (TLSs) are linked to enhanced survival and response rates, but germinal center-like TLSs are challenging to generate in subcutaneous tumors due to rapid clearance of soluble inductive signals. We engineered an injectable supramolecular hydrogel to co-deliver liposome-formulated mRNAs encoding CXCL13 and LIGHT, thereby stabilizing the complexes and extending intratumoral cytokine production. In murine B16.f10, CT26, and 4T1 subcutaneous tumor models, this strategy increased TLS density and maturation, suppressed tumor growth, and prolonged survival. Combination with PD-1 blockade yielded enhanced efficacy antitumor effects, achieving complete tumor regression in some cases. Our results support the development of a novel injectable hydrogel-encapsulated formulation in combination with liposomes for enhancing the efficacy of mRNA therapeutics against cancer.