A review of synergistic strategies in cancer therapy: resveratrol-loaded hydrogels for targeted and multimodal treatment.

Resveratrol (RSV), a natural polyphenol with multifaceted anticancer mechanisms, faces significant pharmacokinetic challenges that limit its clinical utility. This review explores the synergistic integration of RSV with hydrogel-based delivery systems to overcome these limitations and enhance therapeutic efficacy in cancer treatment. Hydrogels, renowned for their tunable physicochemical properties and stimuli-responsive behavior, enable precise spatiotemporal control over RSV release, improving stability, bioavailability, and tumor-targeted delivery. Compared to alternative delivery systems (e.g., liposomes, polymeric nanoparticles), RSV-loaded hydrogels offer distinct advantages in sustained local release and microenvironmental modulation. Advanced hydrogel designs, including pH- and temperature-responsive systems, nanocomposites, and self-healing networks, further amplify RSV's bioactivity by sustaining therapeutic concentrations, modulating tumor microenvironments, and synergizing with chemo-photothermal or immunotherapeutic strategies. Preclinical applications in colorectal cancer and glioblastoma demonstrate RSV-hydrogel platforms' ability to suppress metastasis, reverse chemoresistance, and eradicate cancer stem cells through mechanisms such as Wnt/β-catenin inhibition and ROS-triggered drug activation. While these preclinical results are promising, significant translational challenges remain, including scalable manufacturing, biocompatibility, and clinical translation. Future research priorities include developing more sophisticated stimuli-responsive systems and exploring potential synergies with emerging therapeutic modalities to bridge the gap towards clinical application.