Plant-Based Biomaterials as Bioinstructive Immunomodulators: Design Principles, Mechanisms, and Translational Challenges

Plant-based biomaterials are increasingly recognized as bio-instructive platforms capable of actively modulating immune responses rather than functioning solely as passive structural supports. In this context, the term plant-based is used operationally to denote photosynthetic biomass–derived platforms and includes both terrestrial plants and marine macroalgae, reflecting their shared richness in polysaccharides and secondary metabolites relevant to immune-engineering and regenerative medicine. Current evidence on plant-derived polysaccharides and phytochemicals is critically synthesized, including algal sulfated polysaccharides (fucoidan, alginate, carrageenan), terrestrial plant polysaccharides (e.g., Lycium barbarum and Aloe vera derivatives), and polyphenolic compounds, highlighting their roles as bioinstructive immunomodulators in biomedical contexts.Key immunoregulatory mechanisms are discussed, including macrophage polarization along an M1–M2 functional continuum, pattern-recognition receptor engagement, redox and metabolic regulation, and coordinated crosstalk between innate and adaptive immunity. Particular emphasis is placed on how material structure, molecular weight distribution, and chemical functionalization shape immune cell responses and downstream regenerative outcomes. Advanced delivery strategies, including polysaccharide-based hydrogels, nanocomposites, lipid-based phytosome formulations, and plant-derived extracellular vesicles (EVs), are reviewed as enabling technologies to enhance stability, bioavailability, and spatiotemporal control of plant-derived bioactives. Applications in wound, musculoskeletal, and bone regeneration are summarized with attention to tissue-specific immunological requirements. Key barriers to clinical translation are also addressed, including source variability, batch-to-batch reproducibility, establishment of structure–activity relationships, Good Manufacturing Practice (GMP) compliance, regulatory classification (medical device vs. drug vs. combination product), and ethical considerations related to sourcing and traditional knowledge. For clarity, extracellular vesicles (EVs) are used as an umbrella term encompassing heterogeneous vesicular subpopulations; the term “exosomes” is retained only when supported by subtype-specific characterization, as many studies report mixed EV preparations.