Injectable adhesive hydrogel-drug complexes synchronize the release of chemoimmunotherapy to treat brain tumors in mice

Dion, M. Z.; Cryer, A. M.; Dahis, D.; Dosta, P.; Li, A.; Poley, M.; Puigmal, N.; Ling, I.; Carrasco, S.; Hinojosa, A.; Soria, Y.; Tyler, B.; Brem, H.; Artzi, N.

doi:10.1101/2025.03.31.646388

bioRxiv · 10.1101/2025.03.31.646388

Injectable adhesive hydrogel-drug complexes synchronize the release of chemoimmunotherapy to treat brain tumors in mice

Dion, M. Z.·Cryer, A. M.·Dahis, D.·Dosta, P.·Li, A.·Poley, M.·Puigmal, N.·Ling, I.·Carrasco, S.·Hinojosa, A.·Soria, Y.·Tyler, B.·Brem, H.·Artzi, N.

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Abstract

Brain tumor therapy remains limited by an immunosuppressive, monotherapy-resistant tumor microenvironment and by a paucity of technologies capable of controlling therapy delivery kinetics to the tumor. Here, we describe tissue-adhesive hydrogel-drug complexes (HDCs) for the controlled release of combination therapies synchronized with immune cycle responses following intracranial administration. Injected adhesive HDCs enabled the controlled co-delivery of multiple payloads (chemotherapy, stimulator of interferon genes agonist cyclic dinucleotide nanoparticles, immune checkpoint blockade antibodies), leading to enhanced long-term survival (>80%) and protection from contralateral hemisphere rechallenge after a single dose in multiple syngeneic orthotopic glioblastoma mouse models. Mechanistic studies revealed that tumor rejection is a consequence of reprogramming the tumor microenvironment, driven by three key phases: the initial rapid expression of inflammatory cytokines, notably IFN-{gamma}, and tumor sensitization with antigen exposure during chemoimmunotherapy release, followed by the recruitment and subsequent sustained activation of antigen-presenting and effector cells facilitated by the hydrogels multiweek delivery period. These findings point to tissue-adhesive HDCs, and therapeutic release synchronized with biological responses as key considerations for realizing robust immune activation without provoking toxicity in the treatment of solid tumors.

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Dion, M. Z., Cryer, A. M., Dahis, D., Dosta, P., Li, A., Poley, M., Puigmal, N., Ling, I., Carrasco, S., Hinojosa, A., Soria, Y., Tyler, B., Brem, H., Artzi, N.. 2025-04-05. Injectable adhesive hydrogel-drug complexes synchronize the release of chemoimmunotherapy to treat brain tumors in mice. https://doi.org/10.1101/2025.03.31.646388

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