<i>Ganoderma lucidum</i> -Derived Nanovesicles Attenuate Multiorgan Senescence via Modulation of Oxidative Stress and Inflammation

Aging is a complex and multifactorial biological process characterized by cellular senescence and is a major risk factor for numerous age-related diseases. Developing safe and effective anti-aging interventions remains a significant challenge. In this study, we report the extraction and systematic characterization of <i>Ganoderma lucidum</i>-derived nanovesicles (GLNs), a novel class of fungus-origin nanotherapeutics derived from a traditional medicinal mushroom with established pharmacological activities. We evaluated their physicochemical properties, biocompatibility, biodistribution, and biosafety <i>in vivo</i>. Using a doxorubicin (DOX)-induced acute aging mouse model, we demonstrate that orally administered GLNs significantly mitigate multiorgan injury, as evidenced by reduced serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). GLNs attenuated oxidative stress by decreasing malondialdehyde (MDA) levels through activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) antioxidant pathway. Moreover, GLNs suppressed senescence-associated β-galactosidase activity and downregulated key cell cycle inhibitors p21 and p16, thereby alleviating cellular senescence. Given the interplay between senescence and chronic inflammation, we further investigated the immunomodulatory effects of GLNs. Mechanistically, GLNs inhibited NF-κB activation, reduced pro-inflammatory cytokines (IL-6, TNF-α), and upregulated the anti-inflammatory cytokine IL-10, thereby reprogramming the senescence-associated secretory phenotype (SASP) and attenuating chronic inflammation. Collectively, these findings position GLNs as a safe, orally administrable, and multifunctional nanoplatform with potent antioxidant, antisenescent, and anti-inflammatory activities, offering a promising therapeutic strategy for the prevention and treatment of aging-related disorders.