Natural products nanocarriers: A perspective on precision immunotherapy for melanoma via mitochondrial targeting

Melanoma remains highly aggressive and resistant to current immunotherapies, partly due to mitochondrial metabolic reprogramming, which fosters an immunosuppressive tumor microenvironment. This perspective highlights a novel precision immunotherapy approach using mitochondria-targeted nanocarriers for delivering immunomodulatory natural products. Bioactive phytochemicals like curcumin, berberine, and Raddeanin A possess intrinsic mitochondrial tropism and stimulate immune responses by inducing apoptosis, generating reactive oxygen species, and triggering mitochondrial DNA release. However, their clinical utility is limited by poor bioavailability and specificity. Advanced nanocarriers, including MITO-Porters, polymeric nanoparticles, and mitochondria-homing metal-organic frameworks, enhance selective mitochondrial targeting, bioavailability, and controlled release, significantly amplifying antitumor immunity and reducing off-target toxicity. This integrative strategy combining mitochondrial biology, natural product pharmacology, and nanomedicine holds significant translational potential, offering a promising therapeutic paradigm to overcome melanoma immunoresistance. • Enhancing melanoma immunotherapy with mitochondria-targeted nanocarriers. • Natural phytochemicals reprogram tumor metabolism to boost immunity. • Precise mitochondrial delivery of bioactives via nanocarriers. • Nanocarrier-based strategies synergize with checkpoint blockade.