Nanotechnology-driven strategies for phytochemical-based cancer therapy: Mechanistic and translational perspectives

Cancer remains a major global public health burden, necessitating the development of novel, targeted therapeutic strategies. Capsaicin, a bioactive vanilloid from chili peppers (Capsicum annuum), demonstrates multifaceted antineoplastic activity via TRPV1 activation, intracellular calcium overload, reactive oxygen species (ROS) generation, and inhibition of oncogenic survival pathways. However, its clinical utility is severely hindered by poor aqueous solubility, rapid first-pass metabolism, pungency-induced irritation, and off-target sensory toxicity. Nanotechnology-based delivery platforms including lipid nanocarriers, polymeric nanoparticles, and stimuli-responsive hybrids help overcome these biopharmaceutical limitations by improving stability, prolonging circulation half-life, and promoting tumor-targeted delivery. In preclinical models, capsaicin nanoencapsulation has shown reduced IC₅₀ values, extends drug release duration, and synergizes with conventional chemotherapeutics to overcome multidrug resistance. Despite these promising preclinical outcomes, systemic clinical translation is impeded by real-world hurdles, including human tumor EPR heterogeneity, potential systemic cardiovascular reflex toxicities, and cGMP manufacturing scale-up complexities. Future development may benefit from adopting emerging paradigms namely artificial intelligence (AI)-assisted formulation design, microfluidic synthesis, and biomarker-stratified personalized medicine to successfully translate capsaicin nanoplatforms into multimodal cancer regimens.