Two-stage activated nano-truck enhanced specific aggregation and deep delivery for synergistic tumor ablation

Although nanomedicines have shown high performance in tumor theranostics, their anticancer activity is still limited by the drug delivery capacity, especially lack of targeting capability, poor tumor accumulation, and insufficient tumor deep-penetration. To address this challenge, a high biocompatibility nano-truck (BMP NT) with a two-stage delivery mechanism is designed and developed to achieve the precision therapeutic efficacy of cancer. In view of the enhanced permeability retention (EPR) effect, the surface cleavable layer of BMP NTs can be selectively removed by the overexpressed MMP-2 in a tumor-microenvironment to expose the hydrophobic segments for an induced "braking effect" strategy, resulting in a significant increase in tumor accumulation. Once internalized into cancer cells with the overproduced glutathione (GSH) and H₂O₂, the BMP NTs undergo the second-stage "unloading process" to release Mn²⁺ ions and ultrasmall Bi₂S₃@BSA nanoparticles, and the obtained Mn²⁺ ions can act as a Fenton-like catalyst for continuously catalyzing the endogenous H₂O₂ into highly toxic hydroxyl radicals (˙OH) for CDT. The GSH depletion will in turn improve the Mn²⁺-H₂O₂ reaction, further enhancing CDT efficiency. Meanwhile, the ultrasmall Bi₂S₃@BSA endows BMP NTs with excellent photothermal conversion ability to generate local hyperthermia and accelerate the intratumoral Fenton process, thus leading to an effective tumor therapeutic outcome in the synergistic function of CDT/photothermal therapy (PTT). Moreover, the BMP NTs can be used for in situ self-generation magnetic resonance imaging (MRI) and photoacoustic (PA) imaging to guide precision cancer therapy.