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Autophagy is a pivotal contributing factor to modulate the progression of neurodegenerative diseases. Although naringenin (Nar) has shown beneficial effects against neurodegenerative diseases, its poor solubility and bioavailability have limited its application. The present research aimed to design a nanostructured formulation of Nar to achieve an enhanced therapeutic effect. Herein, Nar‐loaded solid lipid nanoparticles (Nar‐SLNs) were prepared and characterized. Then, PC12 cells were exposed to streptozocin (STZ) and/or Nar and Nar‐SLNs in vitro to clarify the protective effect of Nar and its nanoformulation against STZ‐stimulated neurotoxicity. The empty SLNs and Nar‐SLNs indicated a narrow polydispersity index value with a negative zeta potential. As determined by the scanning electron microscopy images, the nanoparticles had a spherical shape and were less than 20 nm in size. FTIR results demonstrated the interaction between Nar and SLNs and supported the presence of Nar in the nanoparticle. The nanoformulation revealed an initial burst release followed by a sustained release manner. Treatment of PC12 cells with STZ resulted in mitochondrial dysfunction and increased autophagic markers, including LC3‐II, Beclin1, Akt, ATG genes, and accumulation of miR‐21 and miR‐22. Both Nar and Nar‐SLNs pre‐treatment improved cell survival and augmented mitochondrial membrane potential, accompanied by reduced autophagic markers expression. However, Nar‐SLNs were more effective than free Nar. As a result, our findings suggested that SLNs effectively enhance the neuroprotective effect of Nar, and Nar‐SLNs may be a promising candidate to suppress or prevent STZ‐elicited neurotoxicity. Practical applications According to the beneficial effect of Nar in the management of neurodegenerative diseases, we evaluated the protective effect of Nar and Nar‐SLNs against STZ‐stimulated neurotoxicity and analyzed the role of autophagy in STZ‐stimulated neurotoxicity. Our results proposed that Nar‐SLNs could be a promising option for neurological disorders prevention through autophagy suppression.

Rutin (Rut) has been identified as a neuroprotective compound with displayed beneficial effects in Alzheimer’s disease. However, low bioavailability and solubility are the major concerns pertaining to the use of Rut. Aberrant function of autophagy has been found as a well-established participant in the pathogenesis of neuronal degeneration. In the present study, Rut and Rut-loaded solid lipid nanoparticles (Rut-SLNs) were used to protect rat PC12 cells against streptozotocin- (STZ-) induced neurotoxicity. Rut-SLNs were fabricated by a solvent evaporation-ultrasonic method. Depending on the experimental patterns including pretreatment, cotreatment, and posttreatment, PC12 cells were exposed to STZ and desired doses of the SLNs, Rut, and Rut-SLNs. The viability of the cells, the mitochondrial membrane potential (MMP), and the expression of miR-21, miR-22, Akt, ATG5, Beclin1, and LC3 were evaluated by using MTT assay, rhodamine 123 fluorescent dye, and qRT-PCR, respectively. SLN and Rut-SLNs possess the smooth surface with an average size of 117.2 and 176.9 nm, respectively, with a negative zeta potential. The encapsulation efficiency and loading capacity of Rut in SLNs were 90.32% and 49.1%, respectively. The nanoformulation revealed a sustained drug release in vitro up to 72 h and followed Higuchi kinetics. Rut-SLNs displayed a neuroprotective effect by augmenting the viability of PC12 cells and increasing MMP. In addition, Rut-SLNs suppressed autophagy which was stimulated by STZ whereas, the free Rut demonstrated lower effect. Taken together, these results clearly indicated that Rut-SLNs could be a good candidate for the prevention of neurodegenerative diseases.