Two-Stage Targeted Bismuthene-Based Composite Nanosystem for Multimodal Imaging Guided Enhanced Hyperthermia and Inhibition of Tumor Recurrence

A key challenge for nanomedicines in clinical application is to reduce the dose while achieving excellent efficacy, which has attracted extensive attention in dose toxicity and potential risks. It is thus necessary to reasonably design nanomedicine with high-efficiency targeting and accumulation. Here, we designed and synthesized a tetragonal bismuthene-based "all-in-one" composite nanosystem (TPP-Bi@PDA@CP) with two-stage targeting, multimodal imaging, photothermal therapy, and immune enhancement functions. Through the elaborate design of its structure, the composite nanosystem possesses multiple properties including (i) two-stage targeting function of hepatoma cells and mitochondria [the aggregation at the tumor site is 2.63-fold higher than that of traditional enhanced permeability and retention (EPR) effect]; (ii) computed tomography (CT) contrast-enhancement efficiency as high as ∼51.8 HU mL mg^-1(3.16-fold that of the clinically available iopromide); (iii) ultrahigh photothermal conversion efficiency (52.3%, 808 nm), promising photothermal therapy (PTT), and high-contrast infrared thermal (IRT)/photoacoustic (PA) imaging of tumor; (iv) benefitting from the two-stage targeting function and excellent photothermal conversion ability, the dose used in this strategy is one of the lowest doses in hyperthermia (the inhibition rate of tumor cells was 50% at a dose of 15 μg mL^-1and 75% at a dose of 25 μg mL^-1); (v) the compound polysaccharide (CP) shell with hepatoma cell targeting and immune enhancement functions effectively inhibited the recurrence of tumor. Therefore, our work reduces the dose toxicity and potential risk of nanomedicines and highlights the great potential as an all-in-one theranostic nanoplatform for two-stage targeting, integrated diagnostic imaging, photothermal therapy, and inhibition of tumor recurrence.