Dynamic Hydrogel Drug Delivery of mRNA for Enhancing Tertiary Lymphoid Structure Formation and Maturation 2080

Description Tertiary lymphoid structures (TLSs) are lymphoid-like aggregates within the tumor microenvironment, linked to improved cancer prognosis and enhanced immune responses, including immune checkpoint blockade (ICB) therapies. However, inducing mature TLSs is challenging. This study aims to develop a hydrogel drug delivery system to stimulate TLS formation and maturation. We synthesized a hydrogel using 4-(4-chlorophenyl)pyridine-modified hyaluronic acid (HA-CPP) and cucurbit[8]uril (CB[8]). Loaded with cytokines CXCL13 and LIGHT or mRNA-encapsulating liposomes, the hydrogel was injected into cancer-bearing mice. TLS formation and maturation were assessed through immunofluorescence staining, and tumor growth and survival rates were evaluated. We also explored the combined effect of the hydrogel and anti-PD1 ICB therapy on tumor suppression. A single injection of HA-CPP<CB[8] hydrogel containing CXCL13 and LIGHT increased TLS density, facilitated maturation, suppressed tumor growth, and extended survival in an intraperitoneal melanoma mouse model. Combining the hydrogel with anti-PD1 ICB therapy further enhanced tumor suppression, improved survival rates, and strengthened TLS formation. The mRNA-loaded hydrogel effectively induced TLS and combated tumors in various subcutaneous models. The HA-CPP<CB[8] hydrogel-based formulation is an effective synthetic immune niche scaffold, offering a promising strategy for advancing tumor immunotherapy. Funding Sources The research was supported by the National Key Research and Development Program of China (2021YFA0910700).