Albumin–phthalocyanine supramolecular complex enables image-guided and potentiated sonodynamic therapy for glioblastoma

Abstract

Sonodynamic therapy (SDT) is highly attractive for glioma treatment owing to its deep tissue penetration and the ultrasound-triggered transient opening of the blood–brain barrier (BBB). Herein, we report a biomimetic supramolecular strategy that integrates an amphiphilic cationic zinc phthalocyanine (ZnPc) with human serum albumin (HSA) via a green self-assembly process, yielding ZnPc–HSA. Benefiting from tumor metabolic demand and secreted protein acidic and rich in cysteine-mediated albumin uptake, the complex efficiently crosses the BBB and preferentially accumulates in orthotopic gliomas, thus enabling it to be monitored by its inherent near-infrared (NIR) fluorescence. Importantly, supramolecular complexation with HSA unexpectedly and significantly potentiates the sonodynamic activity of ZnPc, an effect that cannot be attributed solely to improved dispersibility. Moreover, compared with the control group, the ZnPc–HSA complex showed enhanced biocompatibility, deeper tumor penetration (∼1.75 times), and a significant increase in reactive oxygen species generation under ultrasound irradiation (∼16.54 times). Consequently, NIR fluorescence–guided SDT based on ZnPc–HSA effectively suppresses glioma growth and significantly prolongs survival in orthotopic mouse models. This work establishes a versatile supramolecular biomimetic platform that integrates BBB penetration, imaging guidance, and amplified sonodynamic efficacy, offering a generalizable strategy for SDT-based treatment of brain disorders. © 2026 Elsevier B.V.