3D Structural Hijacking of Pathological α-Synuclein Fibrillar Architectures by Carbon Dot Nanoeraser Prevents Neurodegeneration

<title>Abstract</title> The pathological aggregation of α-synuclein (α-syn) into fibrillar deposits is a defining neuropathological hallmark of Parkinson’s disease (PD). However, conventional therapeutic strategies aimed at inhibiting α-syn misfolding have faced persistent translational failures, reflecting fundamental limitations in small-molecule approaches within amyloidogenic cascades. Here, we report a misfolded protein-3D-directed nanomedicine paradigm leveraging carbon dots (CDs) for structural reprogramming of α-syn in PD therapeutics. Through hydrothermal conversion of plant-derived organic precursors, we synthesized biocompatible P-CDs exhibiting excellent aqueous stability and tunable photoluminescence. Unexpectedly, P-CDs demonstrate a bifunctional regulatory effect on the aggregation states of α-syn, both suppressing fibrillation and dismantling mature fibrils. Structurally, P-CDs interact with α-syn via a stepwise mechanism: (i) initial non-covalent binding at Lys80 disrupts local fibrils architecture, followed by (ii) the formation of an extensive hydrogen-bond network with N-terminal residues, which promotes large-scale structural disordering and ultimately converts β-sheet-rich aggregates into disordered conformations. Cellular assays demonstrated that α-syn-targeting P-CDs effectively restored impaired mitochondrial function and normalized dysregulated apoptotic pathways in neuronal cells induced by α-syn preformed fibrils. <italic>In vivo</italic> , P-CDs administration significantly attenuated motor dysfunction in hA53T α-syn transgenic mice. Notably, P-CDs exhibited excellent blood-brain barrier penetration capability and favorable biosafety, underscoring their clinical potential for PD therapy. In summary, our findings establish a transformative approach to PD therapy by leveraging CDs to precisely reprogram pathogenic α-syn misfolding, offering a paradigm shift beyond conventional small-molecule drug design.