Abstract: Orthopaedic diseases, including osteoporosis, osteoarthritis, and bone defects, are characterised by dysreg-ulated tissue microenvironments driven by inflammation, oxidative stress, vascular dysfunction, and im-paired cell communication. Strategies targeting single pathways often provide limited durable benefit, highlighting the need for coordinated microenvironmental modulation. Plant-derived exosome-like nano-vesicles (PENs) have emerged as operationally defined bioactive nanovesicles with relevance to orthopae-dic research. While PENs share structural features with mammalian extracellular vesicles, including na-noscale size and lipid bilayer membranes, they are not biogenetically equivalent to mammalian exosomes. Their diverse cargos, low immunogenicity, abundant availability, and intrinsic biological activity may en-able the modulation of osteogenic differentiation, osteoclast activity, inflammatory responses, and angio-genesis. This review synthesises current knowledge on PEN biology, disease-specific therapeutic roles, de-livery strategies, and translational barriers in osteoporosis, osteoarthritis, and bone defect repair. We em-phasise that PEN function and feasibility vary across indications: systemic osteoporosis faces challenges with chronic dosing and standardisation, whereas local applications in osteoarthritis and bone defect repair may offer more tractable translational routes. Engineering approaches, including hydrogels and scaffolds, are key to improving localisation, retention, and controlled presentation. Overall, PENs are best under-stood as complementary bioactive nanovesicles for modulating the orthopaedic microenvironment rather than as direct plant analogues of mammalian exosomes.

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