Swagatam Sahoo, Amulyaratna Behera, Biswajeet Acharya, Debasis Patra
The growing interest in sustainable and biocompatible drug delivery platforms has stimulated research at the interface of natural bioactive compounds and biodegradable nanobiocomposite systems. Although plant-derived molecules such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit diverse pharmacological activities, their clinical utility is often constrained by poor solubility, chemical instability, rapid metabolism, and non-specific biodistribution. Nanotechnology-enabled delivery systems have been explored to mitigate these limitations through enhanced solubilization, protection from degradation, and controlled release; however, most reported benefits remain confined to in-vitro and small-animal studies, with limited clinical validation. Biodegradable nanobiocomposites composed of biopolymers (e.g., chitosan, alginate, and plant-derived gums) and nanoscale reinforcements produced via green synthesis routes have shown favourable encapsulation efficiencies and stimulus-responsive behaviour at the preclinical level. Despite these advances, critical knowledge gaps persist regarding long-term safety, pharmacokinetics, degradation pathways, and reproducibility, particularly for eco-friendly systems derived from natural sources. Furthermore, green synthesis strategies—including plant-mediated, microbial, enzyme-assisted, and polymer-supported approaches—face challenges related to batch-to-batch variability, yield optimisation, and scale-up. This review critically evaluates the current state of biodegradable nanobiocomposites for natural bioactive delivery, highlighting unresolved translational barriers, regulatory considerations, and the need for robust in-vivo and clinical studies before therapeutic claims can be reliably substantiated.