As one of the most common neurodegenerative disorders, Parkinson's disease is a chronic, progressive, and debilitating condition that affects millions of people worldwide. Despite the continuously improved understanding of disease pathogenesis and the identification of numerous potential therapeutic targets, Parkinson's disease management currently relies exclusively on symptomatic treatments that are incapable of halting or slowing down disease progression. The lack of preclinical models that are representative of human biology and physiology is one of the main factors attributed to the limited clinical translation of new therapies. With the advent of induced pluripotent stem cells and gene editing technology, complex and highly customizable in vitro models can be developed to mimic individual pathological characteristics and target specific patient groups, paving the way for personalized medicine approaches. This review summarizes recent developments in advanced in vitro 3D models of Parkinson's disease, with a focus on human cellular models of neurodegeneration that make use of spheroids, organoids, scaffold-based, and microfluidic platforms. Such intricate structures have allowed the recapitulation of key features of Parkinson's disease in vitro, including dopaminergic neuron degeneration, α-synuclein pathology, mitochondrial dysfunction, glial activation, and blood-brain barrier disruption, thus constituting valuable assets in pharmacological and toxicological investigation. While in vitro models cannot yet completely replace animal experimentation in preclinical research, they represent an important step forward in reducing the number of animals used and obtaining human and patient-specific cellular responses, which may contribute to the successful translation of new disease-modifying therapies.
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