Berberine as a Multifunctional Adjuvant in Cancer Therapy: Mechanistic Insights, Nanotechnological Strategies, and Translational Challenges.

Multidrug resistance (MDR) and chemotherapy-associated toxicity remain major challenges limiting the success of cancer treatments. In this context, berberine (BBR), an isoquinoline derivative belonging to the barberry family, has emerged as a promising adjuvant that can enhance the efficacy of chemotherapy while potentially mitigating its side effects. The findings indicate that berberine enhances the therapeutic effect of several drugs, such as doxorubicin, cisplatin, tamoxifen, and 5-fluorouracil, through multiple mechanisms including the inhibition of ABC transporters, regulation of autophagy, and synergistic enhancement of reactive oxygen species generation. Advanced pharmaceutical and nanotechnological formulations, including cyclodextrin complexes, solid dispersions, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, polymeric nanoparticles, chitosan-based systems, and inorganic nanoplatforms, have demonstrated significant improvements in the solubility, stability, cellular uptake, and oral bioavailability of berberine. However, knowledge gaps remain regarding optimal dosage determination, safety assessment in combination therapy, and establishing efficacy in large-scale clinical trials. Incorporating berberine into combination therapy strategies may improve treatment outcomes, overcome drug resistance, and potentially reduce the toxic burden associated with chemotherapy. Therefore, this review provides a comprehensive analytical framework for berberine's potential as an adjuvant, elucidates its mechanistic synergistic interactions with standard therapies, explores pharmaceutical strategies to overcome bioavailability limitations, and suggests future research avenues to further its clinical development.