Triple-responsive catechin-engineered hyaluronic acid micelles for intracellular delivery of doxorubicin

Tumor-targeted and stimuli-responsive nanocarriers have emerged as promising platforms for improving the efficacy and safety of chemotherapy. Herein, we developed a polyethylene glycol- hyaluronic acid-epigallocatechin-3-O-gallate (PEG-HA-EGCG) nanoplatform that integrates polyphenol-mediated drug loading, CD44-targeted delivery, and tumor-responsive doxorubicin (DOX) release. The amphiphilic PEG-HA-EGCG conjugate spontaneously self-assembled into stable micellar nanoparticles comprising a hydrophobic EGCG-rich core and a hydrophilic HA-PEG shell. The abundant aromatic rings and hydroxyl groups of EGCG promoted strong π-π stacking and hydrogen-bonding interactions with DOX, resulting in a high drug-loading efficiency of up to 93% while maintaining nanoparticle stability. Notably, the micelles remained relatively stable under physiological conditions while exhibiting triple-responsive DOX release triggered by acidic pH, reductive conditions, and elevated HAase levels in the tumor microenvironment. The HA shell facilitated CD44 receptor-mediated cellular uptake and enhanced antitumor effects in the 3D spheroid model. Consequently, PEG-HA-EGCG@DOX demonstrated intracellular DOX accumulation and anticancer activity in vitro and achieved tumor growth suppression comparable to free DOX, with reduced systemic toxicity in vivo. These findings demonstrate the potential of PEG-HA-EGCG micelles as a polysaccharide-based nanoplatform integrating high-capacity drug loading, tumor-responsive release, and targeted intracellular delivery for cancer therapy.