Multifunctional Nanoparticles for Theranostics of Protein Misfolding Diseases: A Systematic Review.

Protein misfolding disorders such as Parkinson's disease, Alzheimer's disease, islet amyloidosis, and several other diseases (amyloidosis) are characterized by the pathological accumulation of misfolded proteins that aggregate into toxic oligomers and fibrils. These misfolded proteins trigger oxidative stress, disrupt cellular homeostasis, and ultimately lead to tissue dysfunction. Overcoming the limitations of conventional strategies, multifunctional nanoparticles have emerged as a promising solution for simultaneously detecting, monitoring, and modulating pathogenic protein aggregates, offering a synergistic approach to addressing the multifaceted challenges of protein misfolding diseases. This systematic review examined 85 relevant studies published between 2010 and 2025, identified through PubMed searches. Only experimental studies reporting multifunctional or dual-functional nanoparticles for the theranostics of protein misfolding disorders were included. Data were narratively synthesized according to nanoparticle type, biomedical function, and therapeutic or diagnostic outcomes. The main findings suggest that multifunctional nanoparticles, including metallic, lipid, polymeric, carbon, silica, and hydrogel nanoparticles, can enable real-time monitoring, enhance imaging resolution, improve delivery of anti-amyloidogenic drugs, and mitigate oxidative stress and neuro-inflammation. Some strategies demonstrate potential to cross the blood-brain barrier, selectively bind amyloid aggregates, and provide synergistic theranostic effects. Among these, magnetic nanoparticles are superior because they possess intrinsic diagnostic capabilities and can be used for therapy simultaneously, eliminating the need for additional diagnostic agents. Their multifunctional nature offers several advantages for precision nano-theranostics in managing amyloidosis, though further translational studies are essential to establish scalability, safety, and long-term clinical applicability.