Multifunctional AuPd-cluster nanotheranostic agents with a cascade self-regulating redox tumor-microenvironment for dual-photodynamic synergized enzyme catalytic therapy.

Photodynamic therapy (PDT) has emerged as a promising strategy with higher selectivity and spatiotemporal control than conventional therapies. However, deep hypoxia in tumours has hampered the clinical use of PDT. In this study, a novel multifunctional cluster nanotheranostic agent (AuPd-BSA CN) was fabricated to generate a high amount of reactive oxygen species, regardless of oxygen dependence under 660 nm laser irradiation. The structure and properties of the AuPd-BSA CN were characterised using various technologies. The synthesised AuPd-BSA CN with high biocompatibility served as a superior photodynamic agent, showing prominent antitumour properties under laser irradiation. Additionally, the glucose oxidase-like activity of the AuPd-BSA CN synergistically enhanced the therapeutic performance. Notably, the intrinsic characteristics of the AuPd-BSA CN include dual-modal second near-infrared window fluorescence/photoacoustic imaging capabilities for monitoring and tracking the in vivo tumour therapeutic process. This work provides innovative insights into the AuPd-BSA CN as an "all-in-one" nanoplatform for cancer therapy.

A "Dual-Source, Dual-Activation" Strategy for an NIR-II Window Theranostic Nanosystem Enabling Optimal Photothermal-Ion Combination Therapy.

The activatable imaging technique in the second near-infrared window (NIR-II) utilizes the stimulation of cancer-associated biomarkers for specific imaging to guide precise NIR-II photothermal therapy. However, most activatable nanoprobes with single-source stimulation are insufficient in providing comprehensive information regarding the tumor, severely restricting the therapeutic optimization, especially in NIR-II photothermal therapy (PTT)-based combination therapy. Herein, a "dual-source, dual-activation" strategy-based multifunctional nanosystem, PPAC, is reported as a promising tool for activatable NIR-II fluorescence (FL)/ratiometric photoacoustic (PA) imaging-guided "localization-timing" photothermal-ion therapy (PTIT). A fibroblast activation protein (FAP)-responsive peptide to modify the surface of Pd nanosheets with excellent NIR-II absorption ability can efficiently cross-link BSA-CQ4T to realize NIR-II FL quenching, followed by the loading of Ag to construct the PPAC. Triggered by the specific cleavage with FAP on the perivascular cancer-associated fibroblasts (first source), the PPAC can correspondingly release BSA-CQ4T for rapid fluorescence recovery. The nanosystems are subsequently taken up by tumor cells, where the overexpressed H2 O2 (second source) promotes the oxidation of Ag shell to Ag+ , and further leads the real-time ratiometric PA signals (Ag-PA660/Pd-PA1050) that can monitor the Ag+ ions-related production efficiency and therapeutic performance. Intelligent integration of dual-modality imaging information can comprehensively provide the right time-point and site-specificity for selective NIR-II PTT.

All-in-One Zeolite-Carbon-Based Nanotheranostics with Adjustable NIR-II Window Photoacoustic/Fluorescence Imaging Performance for Precise NIR-II Photothermal-Synergized Catalytic Antitumor Therapy.

In the second near-infrared (NIR-II) biowindow, multimodal optical imaging-guided precise antitumor therapy is a novel strategy for high-efficiency tumor theranostics, however, the all-in-one dual NIR-II photoacoustic (NIR-II PA) and NIR-II fluorescence (NIR-II FL) nanoprobes have been rarely reported mainly due to the short of a simple and universal design approach. Herein, a NIR-II PA/NIR-II FL imaging-adjustable nanozyme (HSC-2) is designed and developed to guide precise photothermal-catalytic synergistic therapy. Based on the ionic liquids adsorption capacity, the electronic structure of zeolite nano-Beta (three dimensional 12-ring pore system and large surface area) can be turned from the indirect band gap to direct band gap via doping carbon in the framework, resulting in outstanding NIR-II FL emission characteristics. As the silicon etching reaction proceeds, HSC-2 shows superior dual-modal NIR-II PA/NIR-II FL imaging performance facilitated by the optimal silicon-to-carbon ratio, simultaneously ensuring efficient tumor photothermal therapy (PTT) in the NIR-II window. Impressively, the peroxidase-mimic activity of HSC-2 in the tumor microenvironment could be further remarkably enhanced by its photothermal effect, leading to excellent synergistic PTT/catalytic therapy. Moreover, the HSC-2 exhibits dual-enzyme activity, and its catalase-like property could effectively eliminate excessive ROS for protection of the normal cells.

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.