Biodegradable 3D Injectable Amino Acid Hydrogels Delivering Immune Adjuvant for Enhancing Immunotherapy in Colon Cancer

Cancer immunotherapy using toll-like receptor agonists (R837) has been extensively investigated and demonstrates potential as an effective adjuvant. Due to the potential for severe side effects associated with R837, the subcutaneous injection of a hydrogel scaffold may enhance its efficacy. Herein, we propose a biodegradable 3D injectable scaffold as an injectable delivery carrier for R837 (R837@Gel), to control the release rate of R837 and be friendly to subcutaneous tissue. Biodegradable 3D injectable amino acid hydrogels were constructed by catalase effect during Fmoc-Phe and Phe₂ substrates. After subcutaneous injection, R837@Gel formed a hydrogel-like component, provided adequate 3D support, and released R837 in order owing to the decomposition of amino acids. Effective CD4⁺ and CD8⁺ T-cell responses were observed, promoted by R837@Gel (p < 0.001). The amino acid hydrogel scaffold exhibited a favorable safety profile and could be degraded successfully. The biodegradable 3D injectable amino acid hydrogels prolonged the action duration of R837 and markedly enhanced the efficacy of PD-1. The 3D amino acid hydrogel scaffold encapsulating R837 in combination with immune checkpoint blockade represents a potent strategy for enhancing antitumor immunotherapy while mitigating systemic toxicity concerns. Moreover, controlled drug administration via subdermal implants has significant potential for reducing the compliance burden associated with frequent dosing. The combination of biocompatibility, ease of modification, and the ability to create a 3D microenvironment makes amino acid hydrogels a valuable tool in the field of regenerative medicine and tissue engineering.