Interleukin-6-taregeted dual-drug nanoparticles enhance glioblastoma chemotherapy by facilitating blood-brain barrier penetration and alleviating cardiotoxicity

Overcoming the blood-brain barrier (BBB) to effectively deliver chemotherapeutics while minimizing systemic toxicity remains a formidable challenge in glioblastoma (GBM) treatment. Herein, amphiphilic liposomal nanoparticles are engineered to encapsulate hydrophobic ursolic acid (UA) and hydrophilic doxorubicin (DOX), surface-functionalized with an interleukin-6 (IL-6) receptor-targeting peptide (I 6 P 8 ) to enable glioma-specific targeting. The I 6 P 8 -modified nanoparticles facilitate BBB penetration and selective glioma accumulation, thereby potentiating the synergistic cytotoxicity of DOX and UA. Furthermore, the interaction between I 6 P 8 and IL-6 not only impairs IL-6-mediated glioma cell proliferation but also enhances therapeutic efficacy. Notably, the dual-drug nanoparticles mitigate DOX-induced cardiotoxicity by attenuating NADPH oxidase 4 (NOX4) expression and promoting nitric oxide (NO) release via UA, thereby preserving myocardial integrity. Comprehensive in vitro and in vivo evaluations confirm that the engineered nanoplatform significantly prolongs median survival of GBM-bearing mice while exhibiting excellent biocompatibility. This study introduces a targeted and low-toxic nanotherapeutic strategy for effective GBM management. Scheme 1 Schematic representation of the synthesis process of DU@L-I and its mechanisms of tumor-killing GBM and reduction of cardiotoxicity. • Dual DOX/UA delivery synergizes anti-glioma efficacy and cardioprotection. • UA attenuates DOX cardiotoxicity via NOX4 inhibition and NO release. • I 6 P 8 -modified liposomes enable BBB penetration and glioma targeting. • IL-6R targeting blocks tumor proliferation and enhances glioma therapy.