Background/Objectives: Parkinson’s disease (PD) is a progressive neuro-degenerative disorder characterized by α-synuclein aggregation, which promotes neuronal death and accelerates neurodegeneration. Small interfering RNA (siRNA) can reduce α-synuclein levels, but its therapeutic potential is limited by poor stability and delivery challenges. Similarly, Selegiline (Sel), a monoamine oxidase-B (MAO-B) inhibitor, has low bioavailability, restricting its effectiveness. This study aims to develop an intranasal (IN) albumin-coated liposomal system (C-Lip_Sel-siSNCA2) for the co-delivery of Sel and α-synuclein-targeting siRNA (siSNCA2) to enhance brain targeting and therapeutic efficacy. Methods: Liposomes were prepared using the ethanol injection method and optimized via D-optimal design for size, charge, and encapsulation efficiency (EE%). The optimized formulation was coated with human serum albumin (HSA) and characterized for stability, cellular uptake, and gene silencing. In vivo pharmacokinetics and pharmacodynamics were assessed in a rotenone-induced PD rat model to evaluate the motor function, biochemical markers, and brain-targeting efficiency. Results: Optimized liposomes had a particle size of 113.5 ± 6.8 nm, zeta potential of 6.2 ± 0.8 mV, and high EE% (Sel: 92.35%; siRNA: 78.66%). Albumin coating increased size to 136.5 ± 10.3 nm and shifted zeta potential to −13.5 ± 1.4 mV, enhancing stability and targeting. IN administration achieved a 3-fold increase in brain area under the concentration-time curve (AUC) versus intravenous delivery. In PD rats, C-Lip_Sel-siSNCA2 improved motor and non-motor functions, restored dopamine levels, enhanced catalase activity, and reduced MAO-B levels, mitigating dopamine degradation and α-synuclein aggregation. Conclusions: This non-invasive, dual-action nanoplatform offers a targeted therapy for PD, combining siRNA gene silencing and MAO-B inhibition, with the potential for clinical translation in neurodegenerative diseases.

Background/objectives: The blood–brain barrier (BBB) significantly limits the treatment of central nervous system disorders, such as schizophrenia, by restricting drug delivery to the brain. This study explores the potential of intranasal clozapine-loaded lipid nanocapsules (IN LNCs_Clo) as a targeted and effective delivery system to the brain. Methods: LNCs_Clo were prepared using the phase inversion technique and characterized in terms of size, zeta potential, entrapment efficiency (EE%), and in vitro drug release. The pharmacokinetic, safety, and pharmacodynamic effects of LNCs_Clo were then evaluated in a rat model through intranasal (IN) administration and compared with those of oral and intravenous (IV) Clo solutions. Results: LNCs_Clo were prepared using a phase inversion technique, resulting in a nanocarrier with a particle size of 28.6 ± 3.6 nm, homogenous dispersion, and high EE% (84.66 ± 5.66%). Pharmacokinetic analysis demonstrated that IN LNCs_Clo provided enhanced Clo brain bioavailability, rapid CNS targeting, and prolonged drug retention compared to oral and intravenous routes. Notably, the area under the curve (AUC) for brain concentration showed more than two-fold and eight-fold increases with LNCs_Clo, compared to IV and oral solutions, respectively, indicating improved brain-targeting efficiency. Safety assessments indicated that LNCs_Clo administration mitigated Clo-associated metabolic side effects, such as hyperglycemia, insulin imbalance, and liver enzyme alterations. Additionally, pharmacodynamic studies showed that LNCs_Clo significantly improved antipsychotic efficacy and reduced schizophrenia-induced hyperactivity, while preserving motor function. Conclusions: These results highlight the potential of IN LNCs_Clo as a novel drug delivery system, offering improved therapeutic efficacy, reduced systemic side effects, and better patient compliance in the treatment of schizophrenia and potentially other CNS disorders.