Flower-Like Nanosensors for Photoacoustic-Enhanced Lysosomal Escape and Cytoplasmic Marker-Activated Fluorescence: Enabling High-Contrast Identification and Photothermal Ablation of Minimal Residual Disease in Breast Cancer.

The clearance of minimal residual disease (MRD) after breast cancer surgery is crucial for inhibiting metastasis and recurrence. However, the most promising biomarker-activated fluorescence imaging strategies encounter accessibility issues of the delivered sensors to cytoplasmic targets. Herein, a flower-like composite nanosensor with photoacoustic (PA) effect-enhanced lysosomal escape and cytoplasmic marker-activated fluorescence is developed to address this challenge. Specifically, the incorporation of Co²⁺ into the synthesis of 2D Zn²⁺-derived metal-organic frameworks enabled rapid dopamine polymerization and deposition. Subsequently, the composite nanoflower (FHN), characterized by an average size of ≈80 nm and petal thickness of ≈6 nm, is formed through the sealing of micropores and simultaneous cross-linking of nanosheets. The pronounced reduction in thermal conductivity of FHN, and superposition of interpetal thermal fields under a pulsed laser (PL), lead to enhanced PA effect and membrane permeability. Thereby, nanosensors efficiently escape from lysosomes resulting in synergistic fluorescence activation by dual-factors (ATP, miRNA-21) and DNA probes installed on FHN. A subsequently high tumor-to-normal tissue signal ratio (TNR) of 17.4 lead to precise guidance of NIR irradiation for efficient MRD eradication and recurrence inhibition. This study provides a new approach for high-contrast identification and precise ablation of MRD based on the synergistic response of endogenous and exogenous factors.