Defect-Engineered Biofunctional Metal Oxide Nanoparticles: Green Synthesis, Structure−Property Relationships, and Next-Generation Biomedical Applications

Abstract Biosynthesis of nano-engineered metal oxides has emerged as a sustainable strategy for producing multifunctional biomedical nanomaterials, using plant extracts, microorganisms, and biopolymers as reducing and stabilizing agents to achieve eco-friendly synthesis with inherent surface functionalization. While numerous studies report successful fabrication and downstream biomedical use of these nanomaterials, the mechanistic links between synthesis-derived structural features, particle size, morphology, crystallinity, defect density, and phytochemical capping and their resulting biological and electrochemical performance remain fragmented and poorly systematized, particularly for biosensing applications where surface chemistry directly governs electron-transfer efficiency and analytical sensitivity. This review addresses that gap by critically synthesizing structure−biofunction relationships across six major green-synthesized metal oxide systems (ZnO, Fe3O4, TiO2, MgO, CeO2, and CuO), integrating their defect chemistry, band structure, and bio-derived surface coatings into a unified framework linking biosynthesis parameters to functional outcomes. Beyond consolidating applications in antimicrobial therapy, ROS-mediated anticancer activity, drug delivery, bioimaging, and tissue engineering, the review places particular emphasis on electrochemical and photoelectrochemical biosensing, extending existing single-oxide, single-analyte studies into a comparative, multi-oxide perspective on how biosynthesis-derived oxygen-vacancy density and surface states collectively determine sensing performance. Key barriers to clinical and analytical translation are identified, including poor reproducibility arising from biological precursor variability, limited control over defect density and phase purity relative to conventional synthesis, inconsistent toxicity evaluation, and the absence of standardized regulatory frameworks. We conclude that advancing green-synthesized metal oxides beyond proof-of-concept status requires standardized biosynthetic protocols, mechanistic structure−activity studies, and data-driven design strategies including hybrid nanocomposites, defect engineering, and AI/ML-assisted optimization to enable reproducible, scalable, and clinically translatable diagnostic and therapeutic platforms.