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Neuroinflammation and mitochondrial function are crucial for neuronal function and survival. SS-31 is a novel mitochondria-targeted peptide antioxidant that reduces mitochondrial reactive oxygen species production, increases ATP generation, protects the integrity of mitochondrial cristae and the mitochondrial respiratory chain, and reduces inflammatory responses. Exploring novel SS-31 derivatives is important for the treatment of neurodegenerative diseases. In this study, nineteen SS-31 derived peptides (5a-5s) were synthesized. Through cellular activity screening, we discovered that 5f and 5g exhibited significantly greater anti-inflammatory activity compared to SS-31, reducing LPS-induced TNF-α levels by 43% and 45%, respectively, at a concentration of 10 μM. Furthermore, treatment with 50 nM of 5f and 5g increased ATP synthesis by 42% and 41% in rotenone-induced HT22 cells and attenuated mitochondrial ROS production by preserving mitochondrial integrity. These findings demonstrate their direct protective effects on neuronal mitochondria. This work highlights the potential of 5f and 5g in the treatment of neurodegenerative diseases associated with inflammation and mitochondrial damage, offering a promising therapeutic avenue for mitochondrial-related conditions such as Alzheimer's disease., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Redox imbalance and abnormal amyloid protein (Aβ) buildup are key factors in the etiology of Alzheimer's disease (AD). As an antioxidant, the hydrogen molecule (H 2 ) has the potential to cure AD by specifically scavenging highly harmful reactive oxygen species (ROS) such as • OH. However, due to the low solubility of H 2 (1.6 ppm), the traditional H 2 administration pathway cannot easily achieve long-term and effective accumulation of H 2 in the foci. Therefore, how to achieve the continuous release of H 2 in situ is the key to improve the therapeutic effect on AD. As a corollary, we designed a rare earth ion doped g-C 3 N 4 upconversion photocatalyst, which can respond to NIR and realize the continuous production of H 2 by photocatalytic decomposition of H 2 O in biological tissue, which avoids the problem of the poor penetration of visible light. The introduction of CoP cocatalyst accelerates the separation and transfer of photogenerated electrons in g-C 3 N 4 , thus improving the photocatalytic activity of hydrogen evolution reaction. The morphology of the composite photocatalyst was shown by transmission electron microscopy, and the crystal structure was studied by X-ray diffractometry and Raman analysis. In addition, the ability of g-C 3 N 4 to chelate metal ions and the photothermal properties of CoP can inhibit Aβ and reduce the deposition of Aβ in the brain. Efficient in situ hydrogen production therapy combined with multitarget synergism solves the problem of a poor therapeutic effect of a single target. In vivo studies have shown that UCNP@CoP@g-C 3 N 4 can reduce Aβ deposition, improve memory impairment, and reduce neuroinflammation in AD mice.

Activities of catalase (CAT) and superoxide dismutase (SOD) of ceria nanoparticles (CeO 2 NPs) provide the possibility for their application in nervous system oxidative stress diseases including Alzheimer's disease (AD). The addition of hot electrons produced by a plasma photothermal effect can expand the photocatalytic activity of CeO 2 to the near-infrared region (NIR), significantly improving its redox performance. Therefore, we coated both ends of gold nanorods (Au NRs) with CeO 2 NPs, and photocatalysis and photothermal therapy in the NIR are introduced into the treatment of AD. Meanwhile, the spatially separate structure enhances the catalytic performance and photothermal conversion efficiency. In addition, the photothermal effect significantly improves the permeability of the blood-brain barrier (BBB) and overcomes the shortcomings of traditional anti-AD drugs. To further improve the therapeutic efficiency, Aβ-targeted inhibitory peptides were modified on the middle surface of gold nanorods to synthesize KLVFF@Au-CeO 2 (K-CAC) nanocomposites. We have verified their biocompatibility and therapeutic effectiveness at multiple levels in vitro and in vivo , which have a profound impact on the research and clinical transformation of nanotechnology in AD therapy.