Supramolecular Filament Hydrogel as a Universal Immunomodulator Carrier for Immunotherapy Combinations

A major challenge of cancer immunotherapy is to develop delivery strategies that can effectively and safely augment the immune system's antitumor response. Here, we report on the design and synthesis of a peptide-based supramolecular filament (SF) hydrogel as a universal carrier for localized delivery of three immunomodulating agents of distinct action mechanisms and different molecular weights, including an aPD1 antibody, an IL15 cytokine, and a STING agonist (CDA). We show that in situ hydrogelation can be triggered to occur upon intratumoral injection of SF solutions containing each of aPD1, IL15, or CDA. The formed hydrogel serves as a scaffold depot for 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 hydrogel led to substantially increased T-cell infiltration and prevented the development of adaptive immune resistance induced by IL15 or CDA alone. These immunotherapy combinations resulted in complete regression of established large GL-261 tumors in all mice and elicited a protective long-acting and systemic antitumor immunity to prevent tumor recurrence while eradicating distant tumors. We believe this SF hydrogel offers a simple yet generalizable strategy for local delivery of diverse immunomodulators for enhanced antitumoral response and improved treatment outcomes.