Engineering Cannabidiol Delivery Systems: From Molecular Encapsulation Mechanisms to Translational Nanomedicine

Abstract Cannabidiol (CBD) is a highly lipophilic phytocannabinoid with therapeutic potential, but its poor aqueous solubility, chemical instability, limited bioavailability, and first-pass metabolism restrict its pharmaceutical performance. An expanding range of nano- and microstructured delivery systems has been developed to rationally engineer CBD transport, stability, release, and biological activity. This review critically evaluates evidence from 55 studies, examining recent advances in CBD delivery platforms, with emphasis on the relationship between fabrication methodology, carrier architecture, molecular encapsulation mechanisms, physicochemical properties, and therapeutic function. Polymeric micelles and nanoparticles, lipid-based nanocarriers, biopolymer matrices, extracellular vesicles, inorganic–organic hybrids, nanoemulsions, liposomal systems, and Pickering emulsions are analyzed in relation to their capacity to improve CBD solubilization, protect against degradation, modulate release kinetics, enhance biodistribution, and support target-enhanced or localized delivery potential. Particular attention is given to the mechanistic contributions of hydrophobic partitioning, hydrogen bonding, electrostatic interactions, physical entrapment, and matrix diffusion to CBD encapsulation and release. Advanced fabrication technologies, including microfluidic nanoprecipitation, flash nanoprecipitation, high-pressure homogenization, microwave-assisted synthesis, and hybrid assembly strategies, further demonstrate progress from empirical formulation toward rational engineering of delivery systems. Across neurological, oncological, inflammatory, dermatological, and autoimmune applications, these platforms show potential to enhance bioavailability and therapeutic performance. Nevertheless, challenges remain regarding formulation standardization, long-term safety, scale-up, reproducibility, regulatory harmonization, and clinical translation. Overall, the field is moving toward structure–function-guided CBD delivery systems in which molecular interactions, carrier architecture, manufacturing technology, and biological barriers are deliberately integrated. This paradigm shift positions CBD nanomedicine as a promising platform for next-generation, application-specific therapeutic delivery.