Tumor microenvironment-remodeling cell membrane biomimetic nanoplatform for activated imaging and cascade-amplified treatment of breast cancer.

Abstract

Introduction: Strategic harnessing and modulation of the tumor microenvironment (TME) can overcome its inherent therapeutic barriers and enhance treatment efficacy. TME hallmarks, including hypoxia, excessive glutathione (GSH), and insufficient H₂O₂, severely limit reactive oxygen species (ROS)-based therapies.

Methods: To address this issue, leveraging the high lactate level in TME, we developed BIMLM (BSA-IR780-MnO₂@LOX@Membrane) as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO₂-coated IR-780 for TME remodeling and self-amplifying ROS generation. BIMLM was fabricated by first preparing MnO₂-coated IR-780 nanoparticles, then immobilizing LOX, and finally cloaking them with tumor cell membranes.

Results: After BIMLM accumulates selectively within tumor tissue, intratumoral excess lactate triggers the sequential therapeutic cascades. Specifically, LOX-catalyzed lactate oxidation generates H₂O₂ to induce metabolic starvation by disrupting energy supply. This H₂O₂ is then decomposed by MnO₂ to produce O₂, which simultaneously facilitates cyclic lactate oxidation and enhances photodynamic therapy (PDT). The resulting Mn²⁺ further triggers a Fenton-like reaction, converting the self-supplied H₂O₂ into •OH and thereby amplifying chemodynamic therapy (CDT). Concurrently, GSH depletion increases cellular susceptibility to ROS, further potentiating both PDT and CDT. Notably, coordinated GSH downregulation and ROS upregulation synergistically trigger ferroptosis, which combines with apoptosis to achieve potent tumor suppression.

Conclusions: Taken together, the nanoplatform reconfigures the TME through lactate depletion, H₂O₂ elevation, hypoxia alleviation, and GSH scavenging. This series of changes creates a self-amplifying cycle that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication. This strategy establishes a promising paradigm for high-efficiency tumor therapy.