Cancer cell membrane-camouflaged CuPt nanoalloy boosts chemotherapy of cisplatin prodrug to enhance anticancer effect and reverse cisplatin resistance of tumor.

The biotoxicity and chemotherapeutic resistance of cisplatin (CDDP) pose a challenge for tumor therapy. Practically, the change in the therapeutic response of tumor from resistance to sensitivity are impressive but challenging. To this end, we propose a strategy of "one stone, three birds" by designing a CuPt nanoalloy to simultaneously eliminate GSH, relieve hypoxia, and promote ROS production for effectively reversing the platinum (IV) (Pt(IV), (c,c,t-[Pt(NH3)2Cl2(OOCCH2CH2COOH)2)) resistance. Notably, the CuPt nanoalloy exhibits ternary catalytic capabilities including mimicking GSH oxidase, catalase and peroxidase. With the subsequent disguise of tumor cell membrane, the CuPt nanoalloy is conferred with homologous targeting ability, making it actively recognize tumor cells and then effectively internalized by tumor cells. Upon entering tumor cell, it gives rise to GSH depletion, hypoxia relief, and oxidative stress enhancement by catalyzing the reaction of GSH and H2O2, which mitigates the vicious milieu and ultimately reinforces the tumor response to Pt(IV) treatment. In vivo results prove that combination therapy of mCuPt and Pt(IV) realizes the most significant suppression on A549 cisplatin-resistant tumor. This study provides a potential strategy to design novel nanozyme for conquering resistant tumor.

Tumor Microenvironment-Activated Nanostructure to Enhance MRI Capability and Nanozyme Activity for Highly Tumor-Specific Multimodal Theranostics.

Copper-based nanozymes exhibit excellent antitumor activity but are easily inactivated due to the disturbance of proteins or other macromolecules with sulfhydryl. A tumor microenvironment-responsive CuMnO@Fe3O4 (CMF) core-shell nanozyme for highly efficient tumor theranostics is developed. A platelet-derived growth factor receptor-ß-recognizing cyclic peptide (PDGFB) target is conjugated to the surface of CMF to fabricate a tumor-specific nanozyme (PCMF). The core-shell nanostructure significantly avoids the oxidation and inactivation of copper-based nanozyme, promoting the antitumor activity of PCMF. The weak acid- and GSH-activated T1 and T2 relaxation rate of PCMF contributes to T1 and T2 dual contrast imaging at the tumor site. In addition, the PCMF disintegrates and produces some metal ions that possess Fenton catalytic activity (i.e., Cu+, Mn2+, and Fe2+) under TME. This process significantly depletes GSH, accelerates Fenton and Fenton-like reactions, enhances cellular reactive oxygen species (ROS) levels, and induces cancer cell apoptosis and ferroptosis. PCMF also exhibits photothermal functions, so it can be used in combined photothermal therapy, ferroptosis therapy, and chemodynamic therapy, improving anticancer activity. This work provides insights into the design of an exquisite nanostructure for high-sensitive and tumor-specific theranostics.

Transition-metal-doped hydrophilic ultrasmall iron oxide modulates MRI contrast performance for accurate diagnosis of orthotopic prostate cancer.

The FDA-approved iron oxide nanocrystals (IONs), as negative magnetic resonance imaging contrast agents (MRICAs), face challenges because of their low relaxation rate and coherent ferromagnetism. Although research has found that metal doping is an efficient approach to improve the magnetic property and MRI contrast performance of IONs, their systemic mechanism has not been fully explained. Herein, we fabricated a series of transition-metal-doped IONs and systemically explored their sizes, structures, and variation in magnetic properties, revealing the oxygen vacancy-mediated MRI contrast enhancement mechanism of transition-metal-doped IONs. Based on these, we found that Zn-doped IONs possess optimal T2 MRI contrast performance and further investigated their potential to diagnose in vivo orthotopic tumor as a T2 contrast agent. The results indicate that the use of Zn-doped IONs significantly enhances T2-weighted MRI signal intensity of orthotopic prostate tumor with low toxicity, which is beneficial for the accurate diagnosis of orthotopic tumor. Collectively, this work clearly illustrates the mechanism of contrast enhancement of transition-metal-doped IONs and provides a novel paradigm for developing a highly efficient T2 contrast agent.

Picomolar thrombin detection by orchestration of triple signal amplification strategy with hierarchically porous Ti3C2Tx MXene electrode material-catalytic hairpin assembly reaction-metallic nanoprobes.

Signal amplification strategies are essential to boost the sensitivity of detecting targeted ions or molecules with important biological functions, while few studies take advantage of signal amplification strategies more than two. As a "proof-of-concept" demonstration, we present the ultrasensitive electrochemical aptasensor for picomolar thrombin detection by synchronous coordination of triple signal amplification strategy. The porous MXene framework (PMXF) with secondary pores is constructed as carrier to increase electrons transfer channels, and thionine (as redox indicator) labelled Au nanorod (AuNR) and hollow Cu-Pt alloy (HCuPtA) are synthesized as the electrical signal amplifiers to enhance the response signals. In the presence of picomolar-level thrombin, catalytic hairpin assembly reactions of DNA are triggered to bridge thionine labelled AuNR or HCuPtA nanoprobes on the PMXF with controllablly scondary pore structures. Under the optimal conditionals, the sandwich-typed aptasensor based on PMXF-5/AuNR shows a more low limit of detection (LOD) of 0.67 pM with a linear range from 2 pM to 10 nM, while PMXF-5/HcuPtA exhibits a more wide linear range from 50 pM to 50 nM with a LOD of 16.67 pM for thormbin. This sensing platform can be customized to analyze other biological or environmental substances at an ultrahigh level by rationally designing DNA sequences of target-binding aptamer.

CuO dot-decorated Cu@Gd2O3 core-shell hierarchical structure for Cu(i) self-supplying chemodynamic therapy in combination with MRI-guided photothermal synergistic therapy.

Theoretically, the Fenton catalytic efficiency of the Cu-based nanoplatform is approximately 160 times that of traditional Fe-based agents. However, the coordination interaction between Cu(ii) and intracellular GSH significantly inhibits the high catalytic activity of Cu(i) generation, dramatically decreasing the Fenton-like catalytic efficiency. Herein, we designed a completely new and highly efficient hierarchical structural nanoplatform to enhance the mimic-peroxidase activity through utilizing comproportionation between CuO and elemental Cu core to self-supply Cu(i). The catalytic rate of this nanoplatform was approximately 55-fold that of traditional Fe-based agents. In a cell assay, this nanoplatform could function as an antagonist of GPX4 and agonist of SOD-1, resulting in intracellular ROS and H2O2 accumulation. Next, the accumulated H2O2 could be quickly catalyzed to highly toxic ˙OH by self-supplying Cu(i), causing strong oxidative stress damage to mitochondria and cell membranes. Under 808 nm laser irradiation, this nanoplatform exhibited a stronger inhibition of tumor growth, and effectively overcame the tumor resistance and recurrence. In addition, this hierarchical structure significantly promoted the interaction between water molecules and gadolinium centers, making TRF-mCuGd possess an ultrahigh T1 MRI contrast performance, and hence, more pathological information of the tumor could be achieved. Overall, this work provides a promising pattern for the design and development of cancer theranostics.

A nanoselenium-coating biomimetic cytomembrane nanoplatform for mitochondrial targeted chemotherapy- and chemodynamic therapy through manganese and doxorubicin codelivery.

The cell membrane is widely considered as a promising delivery nanocarrier due to its excellent properties. In this study, self-assembled Pseudomonas geniculate cell membranes were prepared with high yield as drug nanocarriers, and named BMMPs. BMMPs showed excellent biosafety, and could be more efficiently internalized by cancer cells than traditional red cell membrane nanocarriers, indicating that BMMPs could deliver more drug into cancer cells. Subsequently, the BMMPs were coated with nanoselenium (Se), and subsequently loaded with Mn2+ ions and doxorubicin (DOX) to fabricate a functional nanoplatform (BMMP-Mn2+/Se/DOX). Notably, in this nanoplatform, Se nanoparticles activated superoxide dismutase-1 (SOD-1) expression and subsequently up-regulated downstream H2O2 levels. Next, the released Mn2+ ions catalyzed H2O2 to highly toxic hydroxyl radicals (·OH), inducing mitochondrial damage. In addition, the BMMP-Mn2+/Se nanoplatform inhibited glutathione peroxidase 4 (GPX4) expression and further accelerated intracellular reactive oxygen species (ROS) generation. Notably, the BMMP-Mn2+/Se/DOX nanoplatform exhibited increased effectiveness in inducing cancer cell death through mitochondrial and nuclear targeting dual-mode therapeutic pathways and showed negligible toxicity to normal organs. Therefore, this nanoplatform may represent a promising drug delivery system for achieving a safe, effective, and accurate cancer therapeutic plan.