Electrically controlled hyaluronic acid-based hydrogel for sustained and repeatable metronomic chemotherapy

Achieving sustained plasma drug concentrations within the therapeutic range is essential for effective metronomic chemotherapy, but poor dose control and patient noncompliance remain major clinical challenges. Existing electro-responsive drug delivery systems often have limited clinical utility due to biodegradability, cytotoxicity, or manufacturing complexity. In this study, we present HTZ@D, a biocompatible, biodegradable, and electro-responsive hydrogel composed of hyaluronic acid, tannic acid, and zinc ions (Zn²⁺) loaded with doxorubicin (DOX). Cross-linked using FDA-approved 1,4-butanediol diglycidyl ether (BDDE) and functionalized via TA-Zn²⁺ coordination bonds, HTZ@D enables precise and repeatable drug release triggered by low-voltage AC stimulation (6 Vpp, 500 kHz) while maintaining mechanical integrity and minimizing passive leakage. The system exhibits programmable release profiles for at least 14 days, maintaining drug bioactivity and hydrogel stability. In vitro, HTZ@D selectively induces tumor cell death under stimulation, with minimal toxicity to healthy fibroblasts. In vivo, repeated electrically triggered release maintained the DOX concentration at 10-100 ng mL^-1, matching the regular dose, while significantly inhibiting tumor growth, increasing infiltration of cytotoxic and helper , reducing regulatory T cells, and suppressing angiogenesis. No systemic toxicity or organ damage was observed during the treatment period. This study demonstrates that HTZ is a clinically transferable platform that can overcome the major limitations of current conventional chemotherapy strategies. HTZ's scalable manufacturing, on-demand dosing capabilities, and immunomodulatory effects represent a significant advancement in the fields of programmable drug delivery and precision oncology.