Plant-derived exosome-like nanoparticles as promising biotherapeutic tools: recent advances and challenges

Exosomes, naturally occurring extracellular vesicles with diameters of 30–150 ​nm, have been extensively characterized in mammalian systems. In contrast, plant-derived exosome-like nanoparticles (PELNs) are emerging as versatile therapeutic carriers, offering distinct advantages including intrinsically low immunogenicity, inherent biocompatibility, enhanced biological barrier penetrability, and inherent cell-targeting capabilities. Notably, recent studies reveal that PELNs mediate unprecedented cross-kingdom communication by delivering plant-derived bioactive components to human cells, where they orchestrate immunomodulation, redox homeostasis, and tissue regeneration. This review systematically summarizes cutting-edge advances in PELNs research, emphasizing five critical dimensions: (1) context-dependent biogenesis pathways across plant species, (2) standardized isolation protocols combining ultracentrifugation and density gradient separation, (3) compositional profiles (proteins/lipids/nucleic acids/metabolites), (4) cellular internalization mechanisms, and (5) engineered applications as precision drug delivery platforms. We particularly highlight innovations in PELNs functionalization strategies - including chemical modification, genetic engineering, and biomimetic membrane hybridization - that enhance payload capacity and site-specific delivery. While discussing current limitations such as scalable production bottlenecks and pharmacokinetic characterization gaps, we summarize emerging strategies that aim to bridge botanical nanobiology and clinical practice. By delineating structure-function correlations and quality control standards, this critical review provides insights that may accelerate the development of PELN-based next-generation nanomedicines, ultimately fostering their transition from laboratory breakthroughs to FDA-approved therapeutic solutions. • Plant-derived exosome-like nanoparticles (PELNs) are emerging as natural nanocarriers with broad therapeutic potential. • PELNs exhibit high biocompatibility, low immunogenicity, and efficient capabilities for drug encapsulation and delivery. • Recent advances in PELNs' biogenesis, compositions, uptake mechanisms, and therapeutic applications are summarized. • Current limitations and future directions for regulatory approval and clinical implementation are discussed.