Mitigating Cannabidiol’s Non-Selective Cytotoxicity via Subcellular Organelle Targeting: Exploring Mitochondrial Targeting Potential

Cannabidiol (CBD), a phytocannabinoid from <i>Cannabis sativa</i>, is renowned for its nonpsychoactive properties and therapeutic potential. However, its clinical application is limited by nonselective cytotoxicity, affecting microglia, oligodendrocytes, and other cells. To address this, subcellular organelle-targeting strategies were explored to minimize off-target effects and enhance CBD's therapeutic index. Three organelle-specific conjugates targeting mitochondria, endoplasmic reticulum, and lysosomes were synthesized. Among these, the mitochondria-targeting triphenylphosphonium (TPP)-modified CBD conjugates demonstrated reduced cytotoxicity and enhanced anti-inflammatory activity. Further optimization identified a four-carbon ether chain linker (<b>CBD-TPP-C4</b>) that increased antineuroinflammatory activity by 3-fold and reduced cytotoxicity by 1.6-fold, compared to unmodified CBD. <b>CBD-TPP-C4</b> also elevated mitochondrial ATP levels in vitro, improved mitochondrial morphology and locomotor function in <i>Caenorhabditis elegans</i>, and potentiated morphine analgesia in mice. These findings highlight subcellular targeting as a promising strategy to enhance CBD's safety and efficacy, paving the way for improved therapeutic applications.