Targeted niosomes protect the heart from doxorubicin-induced injury: evidence from oxidative stress, pyroptosis, and apoptosis pathways.

Abstract

Doxorubicin (DOX) is a frontline chemotherapeutic agent whose clinical utility is significantly limited by dose-dependent and often irreversible cardiotoxicity. Niosomal drug delivery systems, owing to their biocompatibility and tumour-targeting potential, often a promising strategy to enhance therapeutic efficacy while mitigating systemic toxicity. In this study, we developed epidermal growth factor receptor (EGFR)-targeted, centuximab-conjugated niosomes co-loaded with DOX and vitexin (NIODVC) and evaluated their cardioprotective efficacy in 4T1 breast tumor-bearing BALB/c mice. Non-targeted niosomes (NIODV) facilitated tumor-specific delivery but were associated with cardiac injury. In contrast, centuximab-modified NIODVC improved formulation stability, enhanced therapeutic effectiveness, and reduced off-target cardiotoxicity. Cardioprotection was supported by normalization of hematological indices, restoration of serum biochemical and oxidative stress markers, preservation of antioxidant competence, and maintenance of myocardial histoarchitecture. Molecular analysis demonstrated upregulation of antioxidant genes (Nrf2, Ho-1, Nqo1, Sod1, Sod2) and suppression of the pro-oxidant gene p67phox. NIODVC also reduced expression of pyroptosis-related mediators (Nlrp3, Caspase-1, Gsdmd, Il-1β, Il-18) and favorably modulated apoptotic balance by increasing Bcl2 and reducing Bax expression relative to NIODV. Notably, intratumoural administration provided grater cardioprotection than intravenous delivery. Taken together, these findings suggest that NIODVC represents a multifunctional nanocarrier capable of enhancing anticancer efficacy while mitigating DOX-induced cardiac injury, Supports its potential for safer breast cancer chemotherapy.

Key Findings

• EGFR-targeted, centuximab-conjugated niosomes co-loaded with doxorubicin and vitexin (NIODVC) improved therapeutic efficacy and reduced cardiotoxicity in breast tumor-bearing mice.
• NIODVC upregulated antioxidant genes including Nrf2, Ho-1, Nqo1, Sod1, and Sod2, while suppressing the pro-oxidant gene p67phox, indicating enhanced antioxidant defense.
• NIODVC reduced pyroptosis-related mediators and favorably modulated apoptotic markers, contributing to cardioprotection compared to non-targeted niosomes.

Clinical Significance

Citation

Vijayapoopathi Singaravel, Kasirajan Kalaiyarasi, Sampath Malathiet al.. Targeted niosomes protect the heart from doxorubicin-induced injury: evidence from oxidative stress, pyroptosis, and apoptosis pathways. 3 Biotech. 2026-Sep.