Exploring the therapeutic potential of phytochemicals: challenges and strategies for clinical translation

Abstract

Background: Phytochemicals exhibit multi-target therapeutic potential with low toxicity, but their clinical translation is limited by poor bioavailability, unclear mechanisms, inadequate models, and structural instability. Addressing these barriers requires integrated strategies that preserve structure-function integrity and improve translational fidelity. Purpose: This review identifies key translational barriers of phytochemicals and proposes integrated, structure-informed strategies combining delivery systems, mechanistic insights, and advanced models to preserve structure-function integrity and enable their application in precision medicine. Study design: A narrative design was adopted to conceptually integrate challenges and solutions in phytochemical translation, emphasizing structural, mechanistic, and pharmacokinetic perspectives to inform clinical application. Methods: Relevant English-language studies from 2015 to 2025 were retrieved from biomedical databases using keywords on phytochemical delivery and mechanisms. Manual screening and citation tracking ensured comprehensive inclusion, including comparative analysis of translational outcomes in key preclinical and clinical studies. Results: Phytochemicals modulate multiple signaling pathways through structurally distinct mechanisms, enabling multi-target activity in complex diseases. However, translation remains limited by poor bioavailability, mechanistic gaps, and nonpredictive models. Structural degradation under physiological conditions further impairs efficacy. Recent advances in nanodelivery, prodrug strategies, omics, and preclinical modeling enhance translational relevance and support repositioning phytochemicals as precision-targeted agents, provided that structure-function integrity is maintained. Conclusion: Preserving structure-function integrity is essential for clinical translation of phytochemicals. Integrated strategies combining delivery optimization, mechanistic clarity, and advanced modeling are needed to overcome translational barriers. These insights are timely given rising clinical interest in phytochemical-based therapeutics and the need for systems that prioritize structural fidelity and personalized application.