Lipid droplets-targeted probe with high-resolution NIR-II fluorescence and photoacoustic angiography for potentiated mild photothermal therapy

This is the authors' abstract. We don't add key points for this paper.

Mild photothermal therapy (mPTT) circumvents the side effects associated with hyperthermic therapy but is hindered by tumor cells' thermal tolerance, primarily driven by upregulated HSP90. Conventional NIR-II probes often suffer from a critical trade-off: enhanced fluorescence imaging brightness comes at the expense of photothermal efficiency, and vice versa. Herein, we developed a lipid droplets-targeted probe 17-AAG/LD/HSA, in which 17-AAG interacted specifically with LD within the human serum albumin (HSA). This interaction boosted its fluorescence intensity by 4.2-fold while retaining a high photothermal conversion efficiency (PCE) of 39.5 %. Molecular docking revealed that 17-AAG and LD bound stably to HSA via multiple interactions, including hydrogen bonds, hydrophobic forces, and sulfur-related interactions, which restricted LD's free rotation and conferred it lipid droplet targeting. In NIR-II fluorescence angiography, 17-AAG/LD/HSA delivered high-definition imaging performance, with a full width at half maximum (FWHM) reaching 0.61 mm and a signal-to-background ratio (SBR) up to 2.46, outperforming blurred LD/HSA images. Concurrently, 17-AAG/LD/HSA displayed excellent NIR-II photoacoustic angiography (FWHM: 0.24 mm, SBR: 41.5), suggesting remarkable dual-modality angiographic capabilities. In cellular and animal studies, 1064 nm laser excitation of the probe specifically downregulated HSP90 in tumor cells, significantly elevating mPTT-induced apoptosis. In U87 MG tumor models, complete tumor regression was achieved without systemic toxicity. Thus, the as-prepared 17-AAG/LD/HSA breaks through existing limitations by precisely regulating energy distribution for synergistic imaging and mPTT, while overcoming thermal tolerance via HSP90 inhibition.