Engineering Strategies for Plant-Derived Extracellular Vesicles: Modification, Drug Delivery Performance, and...

Plant-derived extracellular vesicles (PDEVs) are a novel category of natural nanocarriers with widespread availability, low immunogenicity, high biocompatibility, and inherent pharmacological activity. These features underscore their value as dual-function systems capable of serving as both carriers and bioactive agents. Unlike previous reviews that focused primarily on disease-specific applications or on individual engineering techniques, this review established a conceptual framework integrating three interconnected dimensions: (i) engineering strategies that address the inherent limitations of PDEVs (targeting, stability, loading efficiency); (ii) the carrier-performance-synergy paradigm linking PDEV composition to therapeutic outcomes; and (iii) gel-composite design principles that transform local retention into a controllable delivery platform. This review delves into various engineering methodologies, including targeted modification, enhanced stability, and optimized drug loading, while elucidating the performance characteristics of PDEVs as drug carriers, focusing on their protective, targeting, and controlled-release properties. It notably investigates the synergistic interactions between the intrinsic bioactivity of PDEVs and the drugs they deliver. Furthermore, this review highlights advanced applications of PDEV gel composites in localized drug delivery, specifically emphasizing their clinical potential for treating dermatological conditions. Finally, it highlights the current challenges faced by PDEVs and anticipates future research directions, such as synthetic biology, multi-omics analysis, and clinical translation. This review provides a theoretical framework for the rational design and clinical translation of PDEVs. It thereby promotes their innovative development in precision nanomedicine.