Next-Generation Theragnostic Gold Nanoparticles: Sustainable Bioengineering Strategies for Enhanced Stability and Biocompatibility

The stability and dispersity of gold nanoparticles (AuNPs) against diverse biological, physicochemical, and physiological transformations while retaining biocompatibility are fundamental for their myriad utilization in various theragnostic applications. This comprehensive review provides a comprehensive analysis of the principles governing the colloidal stability of AuNPs and the factors influencing their physicochemical, chemical, and biological stability. Key parameters such as resistance to aggregation in aqueous and biological medium, stability under physiological pH and ionic conditions, and the impact of protein corona formation on nanoparticle functionality are illustrated in detail. Diverse surface engineering strategies that are employed for achieving ultra-stable AuNPs, including electrostatic and steric stabilization methods are explored. Attention is also given to the widely used polymers like polyethylene glycol, polyvinylpyrrolidone, polyethylenimine, poly(lactic-co-glycolic acid), and polydopamine, which have demonstrated significant efficacy in enhancing nanoparticle stability under physiological conditions along with their controversies and negative impacts. Alternatively, the emergence of safe bioconjugation strategies using proteins, peptides, and nucleic acids that offer promising pathways to improve biocompatibility and facilitate targeted applications are discussed. We also highlight the emerging sustainable approaches for AuNP stabilization using resilient biomolecules such as glycans, lipids, and plant-derived phytochemicals. Innovations like fish-scale-derived proteins and glycan-based coatings showcase the potential of biogenic methodologies to provide ultra-stable nanoparticles with minimal environmental impact. By advancing sustainable and innovative surface engineering strategies, this review underscores the potential for ultra-stable, biocompatible AuNPs to drive safer, more effective solutions in nanomedicine while reducing the ecological footprint of their production. The objective of this review is to systematically present both conventional and emerging strategies for stabilizing AuNPs, with a particular focus on sustainable, biocompatible, and high-performance approaches that support safer and more effective applications in nanomedicine. Unlike existing reviews that primarily focus on classical polymer-based stabilization or biomedical applications alone, this work uniquely integrates a critical evaluation of conventional polymers with a comprehensive overview of innovative, eco-friendly biogenic alternatives. It emphasizes the dual imperative of performance and sustainability, offering a forward-looking framework for designing next-generation AuNPs with minimal ecological impact. © 2025 Elsevier B.V.