Flefil_2026_Probiotics.Antimicrob.Proteins__

C-phycocyanin (C-PC) is a promising anti-aging nutraceutical due to its antioxidant and anti-inflammatory properties; however, its instability under acidic conditions limits its efficacy, necessitating advanced formulation strategies. This study evaluated the anti-aging potential of novel enteric C-PC nanoparticles (NPs) co-delivered with Pediococcus pentosaceus in a D-galactose-induced aging model in male Wistar rats. C-PC was extracted from microalgal biomass and encapsulated into Eudragit((a)) S100 nanoparticles. Particle size, encapsulation efficiency, zeta potential, pH-responsive release, and morphology were characterized. Aging was induced in male Wistar rats using D-galactose. Oxidative stress markers, neurotransmitters, acetylcholine metabolism, behavioral performance, and brain histopathology were assessed following treatment with C-PC nanoparticles with or without probiotic co-supplementation. C-PC was extracted from 2.5 g dry biomass with a yield of 31.02% and a purity ratio (A(620)/A(280)) of 0.704, then successfully encapsulated into Eudragit((a)) S100 nanoparticles (211.4 +/- 8.1 nm; encapsulation efficiency 63.7 +/- 4.16%; zeta potential - 20.4 +/- 3.7 mV) exhibiting pH-responsive release and uniform nanoscale morphology. D-galactose-induced aging markedly increased lipid peroxidation (MDA + 362.8%), depleted antioxidant defenses (GSH - 78.96%, TAC - 79.22%), reduced monoaminergic neurotransmitters (48.11-52.86%), decreased acetylcholine (- 66.12%), elevated acetylcholinesterase activity (+ 163.45%), impaired cognition and motor function (T-maze + 136%, beam balance + 69.6%), and caused severe brain histopathology. Treatment with C-PC nanoparticles, alone or combined with P. pentosaceus, significantly alleviated oxidative stress (MDA 112.2-196.4%, GSH 20.6-38.8%, TAC 42.9-50.7%), restored neurotransmitters (16-40.3%), improved cholinergic balance, enhanced behavioral performance, and preserved brain structure. These preclinical findings introduce C-PC nanoparticle-probiotic co-supplementation as a promising nutraceutical strategy against aging-associated neurodegeneration.