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Effective siRNA delivery to neurons, however, poses challenges due to premature nucleic acid degradation and unspecific delivery. Chitosan\u2010based delivery systems, noted for their biocompatibility, face limitations such as low transfection efficiency and lack of neurotropism. Building on the previous successes with neuron\u2010targeted DNA delivery using chitosan, a novel approach for siRNA delivery aimed at PTEN downregulation is proposed. This involves using thiolated trimethyl chitosan (TMCSH)\u2013based siRNA nanoparticles functionalized with the neurotropic C\u2010terminal fragment of the tetanus neurotoxin heavy chain (HC) for efficient delivery to peripheral and central neurons. These polyplexes demonstrate suitable physicochemical properties, biocompatibility, and no adverse effects on neuronal electrophysiology. Diverse neuronal models, including 3D ex vivo cultures and microfluidics, confirm the polyplexes\u2019 efficiency and neurospecificity. HC\u2010functionalization significantly enhances neuronal binding, and live cell imaging reveals fivefold faster retrograde transport along axons. Furthermore, siRNA delivery targeting PTEN promoted axonal outgrowth in embryonic cortical neurons. 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