Cell-targeted nanocomplex facilitates direct reprogramming of astrocytes into dopaminergic neurons in Parkinson's...

Direct in vivo reprogramming of dopaminergic neurons represents a transformative approach for neuroregeneration, enabling the generation of new functional dopamine neurons in the brain and offering direct therapeutic potential for Parkinson's disease. However, the complex milieu of the adult brain, where persistent barriers to cellular specificity remain, continues to challenge the efficiency and success of conversion into induced dopaminergic (iDA) neurons. To overcome these limitations, we developed astrocyte-targeted system for conversion into iDA neurons using functionalized gold nanoparticle-based nanocomplexes with cell-specific ligands for targeted transdifferentiation. This system facilitated robust astrocyte-to-dopaminergic neuron conversion both in vitro and in vivo, with strong expression of dopaminergic markers exclusively in targeted astrocytes. Moreover, this astrocyte-targeted nanocomplex promoted the activation of successful reprogramming pathways, further enhancing reprogramming efficacy. Application of this cell-targeted nanocomplex system in a 6-OHDA-induced Parkinson's disease mouse model resulted in substantial increases in newly generated dopaminergic neurons, restoration of striatal dopamine levels, and significant improvements in multiple motor functions. These findings establish a cell-targeted, functionalized nanocomplex capable of highly selective in vivo reprogramming, offering a promising and targeted therapeutic strategy for Parkinson's disease. STATEMENT OF SIGNIFICANCE: Direct reprogramming of glial cells into dopaminergic neurons represents a promising therapeutic strategy for Parkinson's disease, although achieving selective and efficient conversion in the adult brain remains challenging. Here, we report astrocyte-targeted induced dopaminergic neurons reprogramming in vivo using functionalized gold nanoparticle nanocomplexes. This platform enables efficient conversion of astrocytes into functional dopaminergic neurons, leading to restored dopamine levels and improved motor function in a Parkinson's disease mouse model. Unlike non-targeted approaches, our system achieves high targeting precision and successful direct cellular conversion. Collectively, these results demonstrate that precision-engineered, cell-selective biomaterials can effectively guide cell fate in the brain, representing a significant step toward safe and targeted regenerative therapies through direct reprogramming.