Supramolecular Filament Hydrogel as a Universal Immunomodulator Carrier for Immunotherapy Combinations

A major challenge of cancer immunotherapy is to developdeliverystrategies that can effectively and safely augment the immune system'santitumor response. Here, we report on the design and synthesis ofa peptide-based supramolecular filament (SF) hydrogel as a universalcarrier for localized delivery of three immunomodulating agents ofdistinct action mechanisms and different molecular weights, includingan aPD1 antibody, an IL15 cytokine, and a STING agonist (CDA). Weshow that in situ hydrogelation can be triggeredto occur upon intratumoral injection of SF solutions containing eachof aPD1, IL15, or CDA. The formed hydrogel serves as a scaffold depotfor sustained and MMP-2-responsive release of immunotherapeutic agents,achieving enhanced antitumor activities and reduced side effects.When administered in combination, the aPD1/IL15 or aPD1/CDA hydrogelled to substantially increased T-cell infiltration and prevented thedevelopment of adaptive immune resistance induced by IL15 or CDA alone.These immunotherapy combinations resulted in complete regression ofestablished large GL-261 tumors in all mice and elicited a protectivelong-acting and systemic antitumor immunity to prevent tumor recurrencewhile eradicating distant tumors. We believe this SF hydrogel offersa simple yet generalizable strategy for local delivery of diverseimmunomodulators for enhanced antitumoral response and improved treatmentoutcomes.

Automated summary

A peptide-based supramolecular filament hydrogel was designed and synthesized as a carrier for localized delivery of three immunomodulating agents. The hydrogel acted as a depot for sustained release of the immunotherapeutic agents, resulting in enhanced antitumor activities and reduced side effects. Combination therapy using the hydrogel led to complete regression of tumors and elicited a systemic antitumor immunity. This hydrogel offers a simple and generalizable strategy for local delivery of immunomodulators, improving treatment outcomes.