Olmesartan-Loaded PLGA Nanoparticles Attenuate Methotrexate-Induced Kidney Injury: Association with the AT1R/ERK1/2 Signaling Axis

Background/Objectives: Methotrexate (MTX) is an effective antineoplastic and immunosuppressive agent whose clinical use can be limited by nephrotoxicity. Increasing evidence suggests that dysregulated angiotensin II-mediated signaling contributes to MTX-induced renal injury. Olmesartan (OLM), an angiotensin II type 1 receptor (AT1R) blocker, possesses renoprotective properties; however, its therapeutic efficacy may be limited by suboptimal pharmacokinetics and tissue deli\\very. This study aimed to develop OLM-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (OLM-PLGA) and investigate their nephroprotective efficacy and underlying molecular mechanisms in MTX-induced nephrotoxicity. Methods: OLM-PLGA nanoparticles were prepared and evaluated for their physicochemical characteristics. The in vivo nephroprotective effects of OLM-PLGA were investigated in male Sprague–Dawley rats, which were allocated into four groups: OLM (10 mg/kg), OLM-PLGA (10 mg/kg), MTX-treated, and normal control. Renal function, oxidative stress, inflammation, apoptosis, and fibrosis were assessed, together with renal gene expression of AT1R and extracellular signal-regulated kinase 1/2 (ERK1/2). Results: Compared with free OLM, OLM-PLGA provided superior protection against MTX-induced renal dysfunction and oxidative stress, as evidenced by improved renal function and enhanced antioxidant defense. OLM-PLGA also exerted greater anti-inflammatory and anti-apoptotic effects and attenuated renal fibrotic changes, accompanied by reduced renal expression of α-smooth muscle actin and collagen. These protective effects were associated with decreased AT1R gene expression and suppression of downstream ERK1/2 signaling. Conclusions: PLGA-based nanoencapsulation enhanced the nephroprotective efficacy of OLM against MTX-induced nephrotoxicity and was associated with the modulation of the AT1R/ERK1/2 signaling axis. OLM-PLGA may therefore represent a promising nanotherapeutic approach for improving OLM delivery and renal protection during MTX treatment.