Engineering a versatile oncotherapy nanoplatform integrating both diagnostic and therapeutic functions has always been an intractable challenge in targeted cancer treatment. Herein, to actualize the theme of precise medicine, a nanoplatform is developed by anchoring Mn-Cdots to doxorubicin (DOX)-loaded mesoporous silica-coated gold cube-in-cubes core/shell nanocomposites and further conjugating them to a Arg-Gly-Asp (RGD) peptide (denoted as RGD-CCmMC/DOX) to achieve an active-targeting effect. Under 635 nm irradiation, the nanoplatform acts as oxygen nanogenerator that produces O2 in situ and amplifies the content of singlet oxygen (1O2) in the hypoxic tumor microenvironment (TME), which has been demonstrated to attenuate tumor hypoxia and synchronously enhance photodynamic efficacy. Moreover, the gold cube-in-cube core in this work has been proven as a photothermal agent for hyperthermia, which exhibits a favorable photothermal effect with a 65.6% calculated photothermal conversion efficiency under 808 nm irradiation. In addition, the nanoplatform achieves heat- and pH-sensitive drug release with precise control to specific-tumor sites, executing combined chemo-phototherapy functions. Besides, it functions as a multimodal bioimaging agent of photothermal, fluorescence, and magnetic resonance imaging for the accurate diagnosis and guidance of therapy. As validated by in vivo and in vitro assays, the TME-responsive nanoplatform is highly biocompatible and effectively obliterates 4T1 tumor xenografts on nude mice after triple-synergetic treatment. This work presents a rational design of versatile nanoplatforms, which modulate the TME to enable high therapeutic performance and multiplexed imaging, which provides an innovative paradigm for targeted tumor therapy.

The limited efficacy of “smart” nanotheranostic agents in eradicating tumors calls for the development of highly desirable nanoagents with diagnostics and therapeutics. Herein, to surmount these challenges, we constructed an intelligent nanoregulator by coating a mesoporous carbon nitride (C3N4) layer on a core–shell nitrogen-doped graphene quantum dot (N-GQD)@hollow mesoporous silica nanosphere (HMSN) and decorated it with a P-PEG-RGD polymer, to achieve active-targeting delivery (designated as R-NCNP). Upon irradiation, the resultant R-NCNP nanoregulators exhibit significant catalytic breakdown of water molecules, causing a sustainable elevation of oxygen level owing to the C3N4 shell, which facilitates tumor oxygenation and relieves tumor hypoxia. The generated oxygen bubbles serve as an echogenic source, triggering tissue impedance mismatch, thereby enhancing the generation of an echogenicity signal, making them laser-activatable ultrasound imaging agents. In addition, the encapsulated photosensitizers and C3N4-layered photosensitizer are simultaneously activated to maximize the yield of ROS, actualizing a triple-photosensitizer hybrid nanosystem exploited for enhanced PDT. Intriguingly, the N-GQDs endow the R-NCNP nanoregulator with a photothermal effect for hyperthemia, making it exhibit considerable photothermal outcomes and infrared thermal imaging (IRT). Importantly, further analysis reveals that the polymer-modified R-NCNPs actively target specific tumor tissues and display a triple-modal US/IRT/FL imaging-assisted cooperative PTT/PDT for real-time monitoring of tumor ablation and therapeutic evaluation. The rational synergy of triple-model PDT and efficient PTT in the designed nanoregulator confers excellent anticancer effects, as evidenced by in vitro and in vivo assays, which might explore more possibilities in personalized cancer treatment.

No abstract

Amyloid β-peptide oligomer (AβO) is widely acknowledged as the promising biomarker for the diagnosis of Alzheimer's disease (AD). In this work, we designed a three-dimensional (3D) DNA walker nanoprobe for AβO detection and real-time imaging in living cells and in vivo. The presence of AβO triggered the DNAzyme walking strand to cleave the fluorophore (TAMRA)-labeled substrate strand modified on the gold nanoparticle (AuNP) surface and release TAMRA-labeled DNA fragment, resulting in the recovery of fluorescent signal. The entire process was autonomous and continuous, without external fuel strands or protease, and finally produced plenty of TAMRA fluorescence, achieving signal amplification effect. The nanoprobe enabled the quantitative detection of AβO in vitro, and the limit of detection was 22.3 pM. Given the good biocompatibility of 3D DNA walker nanoprobe, we extended this enzyme-free signal amplification method to real-time imaging of AβO. Under the microscope, nanoprobe accurately located and visualized the distribution of AβO in living cells. Moreover, in vivo imaging results showed that our nanoprobe could be used to effectively distinguish the AD mice from the wild-type mice. This nanoprobe with the advantages of great sensitivity, high specificity, and convenience, provides an outstanding prospect for AD's early diagnosis development.

No abstract