Ferromagnetic ordering correlated strong metal-oxygen hybridization for superior oxygen reduction reaction activity.

The efficiency of transition-metal oxide materials toward oxygen-related electrochemical reactions is classically controlled by metal-oxygen hybridization. Recently, the unique magnetic exchange interactions in transition-metal oxides are proposed to facilitate charge transfer and reduce activation barrier in electrochemical reactions. Such spin/magnetism-related effects offer a new and rich playground to engineer oxide electrocatalysts, but their connection with the classical metal-oxygen hybridization theory remains an open question. Here, using the MnxVyOz family as a platform, we show that ferromagnetic (FM) ordering is intrinsically correlated with the strong manganese (Mn)-oxygen (O) hybridization of Mn oxides, thus significantly increasing the oxygen reduction reaction (ORR) activity. We demonstrate that this enhanced Mn-O hybridization in FM Mn oxides is closely associated with the generation of active Mn sites on the oxide surface and obtaining favorable reaction thermodynamics under operating conditions. As a result, FM-Mn2V2O7 with a high degree of Mn-O hybridization achieves a record high ORR activity. Our work highlights the potential applications of magnetic oxide materials with strong metal-oxygen hybridization in energy devices.

An NIR-Fluorophore-Based Theranostic for Selective Initiation of Tumor Pyroptosis-Induced Immunotherapy.

Pyroptosis is an inflammatory form of programmed cell death that can effectively eliminate malignant cells and boost anticancer immunity. However, most of the current pyroptosis inducers lack cell selectivity, which may cause severe side effects for cancer therapy. In this work, for the first time, the authors discovered that the commonly used near-infrared (NIR) fluorogenic hemicyanine (CyNH2 ) induces pyrolysis to kill cancer cells and boost antitumor immunity. Cancer cells overexpressing the NAD(P)H: quinone oxidoreductase isozyme 1 (NQO1)-responsive theranostic (NCyNH2 ) are designed for selective cell pyroptosis and are nonfluorescent with low toxicity before activation. In the presence of NQO1, the fluorescence of CyNH2 is restored and can selectively initiate pyroptosis of cancer cells and further lead to systemic antitumor immunity activation for solid tumor therapy. Thus, this fluorogenic NIR dye may represent a novel theranostic agent for the selective initiation of tumor pyroptosis.

Self-boosting stimulus activation of a polyprodrug with cascade amplification for enhanced antitumor efficacy.

The use of polyprodrugs, which bind drugs to polymer chains through responsive linkers, is a potential technique for cancer therapy; however, a lack of endogenous triggering factors limits drug activation in tumor tissue. Herein, we rationally created a reactive oxygen species (ROS)-sensitive polyprodrug (TSCA/DOX) with cascade amplification of triggering agents and drug activation by incorporating both an ROS signal amplifier (TACA) and a drug activation amplifier (SIPDOX) into a delivery system. Endogenous ROS as a triggering mechanism kicked off the initial circulation phase to increase intracellular ROS signals. Subsequently, the enhanced ROS initiated the second degradation step, allowing the polyprodrug SIPDOX to fracture spontaneously in a domino-like fashion, resulting in self-accelerated drug activation in tumor tissue. Therefore, the polyprodrug created in this study with cascade amplification of drug activation holds great promise for effective cancer treatment.

Self-amplified chain-shattering cinnamaldehyde-based poly(thioacetal) boosts cancer chemo-immunotherapy.

The selective activation of stimuli-responsive polymers in the tumor microenvironment is a great concern to achieve intelligent cancer therapy, but most of them show inadequate response due to insufficient endogenous triggering agents. Herein, we rationally designed a reactive oxygen species (ROS)-responsive cinnamaldehyde (CA)-based poly(thioacetal), consisting of ROS-responsive thioacetal (TA) and ROS-generating agent CA, with self-amplified chain-shattering polymer degradation. The mechanism of self-amplified chain-shattering is that endogenous ROS as a triggering agent facilitates chain cleavage of TA with the release of CA, which in turn produces more ROS through mitochondrial dysfunction, resulting in an exponential polymer degradation cascade. The polymer can be further modified with anticancer drug doxorubicin (DOX) for cooperative amplification of oxidative stress and immunogenic cell death (ICD) of tumor cells, thereby boosting the effect of chemo-immunotherapy. The self-amplified chain-shattering polymer designed in this work holds great promise in developing stimuli-responsive polymers for efficient drug delivery. STATEMENT OF SIGNIFICANCE: This study presented an approach to utilize self-amplified chain-shattering cinnamaldehyde-based poly (thioacetal) as a drug delivery system to restrain tumor growth and boost chemo-immunotherapy. The endogenous ROS as a triggering agent initiates the chain cleavage with the release of CA, which in turn produces ROS through mitochondria dysfunction, resulting in an exponential polymer degradation cascade and rapid drug release.

Tumor-acidity and bioorthogonal chemistry-mediated construction and deconstruction of drug depots for ferroptosis under normoxia and hypoxia.

Mounting evidence shows that tumor hypoxia stress promotes tumor invasion and metastasis and induces therapeutic resistance. Oxygen-independent Fenton reaction, which refers to the iron-catalyzed conversion of endogenous hydrogen peroxide (H2O2) to hydroxyl radical (·OH), has been designed for ferroptosis therapy. Nevertheless, the treatment efficiency is compromised by limited H2O2 content and limited tumor retention and penetration of nanoparticles. Herein, we designed a tumor-acidity and bioorthogonal chemistry mediated construction and deconstruction of drug depots for tumor ferroptosis under normoxia and hypoxia. Briefly, the dendritic poly(amidoamine) (PAMAM, G4) was modified using cinnamaldehyde (CA) to deplete GSH and increase H2O2 levels, and ferrocene (Ferr) served as Fenton reaction catalyst to generate PFC. Subsequently, PFC was modified with maleic acid amide with slow pH-response rate and poly(2-azepane ethyl methacrylate) (PAEMA) with rapid pH-response rate, accompanied with highly efficient bioorthogonal chemistry to construct and deconstruct drug depots for enhanced tumor retention and penetration. The small-sized PFC potentially induced H2O2 self-supplied ferroptosis under normoxia and hypoxia. In sum, this work utilizes two tumoral acidity-responsive groups with different response rates and highly efficient bioorthogonal click chemistry, which paves a way for ferroptosis and provides a general drug delivery strategy with enhanced tumor retention and penetration. STATEMENT OF SIGNIFICANCE: Oxygen independent Fenton reaction refers to the conversion of endogenous H2O2 to ·OH which has been designed for ferroptosis therapy. Nevertheless, limited H2O2 level and abundant GSH in tumor cells could both compromise the treatment efficiency. Herein, we developed a tumor-acidity and bioorthogonal chemistry mediated construction and deconstruction of drug depots, which elevate the intracellular H2O2 level and deplete GSH for tumor ferroptosis under normoxia and hypoxia microenvironment. This work utilizes two tumoral acidity response groups with different response rates and highly efficient bioorthogonal click reactions, which paves a way for tumor cell ferroptosis and provides a general drug delivery strategy for enhanced tumor accumulation and penetration.

Self-catalyzed tumor ferroptosis based on ferrocene conjugated reactive oxygen species generation and a responsive polymer.

In this work, we developed a ferroptosis self-catalyst, PTAF, exhibiting self-catalyzed ferroptosis for enhanced cancer therapy. Briefly, synergistic actions of self-catalyzed ˙OH accumulation and GPX4 indirect inactivation based on the establishment of the ROS self-catalytic loop effectively induced tumor ferroptosis, which provided a novel approach for enhanced tumor therapy.

Cinnamaldehyde-based poly(thioacetal): A ROS-awakened self-amplifying degradable polymer for enhanced cancer immunotherapy.

Although stimuli-responsive polymers have emerged as promising strategies for intelligent cancer therapy, limited polymer degradation and insufficient drug release remain a challenge. Here, we report a novel reactive oxygen species (ROS)-awakened self-amplifying degradable cinnamaldehyde (CA)-based poly(thioacetal) polymer. The polymer consists of ROS responsive thioacetal (TA) group and CA as the ROS generation agent. The self-amplified polymer degradation process is triggered by endogenous ROS-induced cleavage of the TA group to release CA. The CA released then promotes the generation of more ROS through mitochondrial dysfunction, resulting in amplified polymer degradation. More importantly, poly(thioacetal) itself can trigger immunogenic cell death (ICD) of the tumor cells and its side chains can be conjugated with indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor to reverse the immunosuppressive tumor microenvironment for synergistic cancer immunotherapy. The self-amplified degradable poly(thioacetal) developed in this work provides insights into the development of novel stimulus-responsive polymers for enhanced cancer immunotherapy.

Amplification of tumor oxidative stresses by Poly(disulfide acetal) for multidrug resistance reversal.

Discovering new strategies to overcome multidrug resistance (MDR) is still urgently needed. MDR is associated with the overexpression of transmembrane efflux pumps, and adenosine triphosphate (ATP) is indispensable for its function. Herein, we developed a pH- and glutathione (GSH)-responsive amphiphilic poly(disulfide acetal) (PCS) containing cinnamaldehyde (CA) and disulfide groups that amplify oxidative stress for anticancer drug delivery and simultaneously overcome drug resistance in cancer cells. Reactive oxygen species (ROS)-generating CA and the disulfide groups to deplete GSH and synergize to amplify oxidative stress in cancer cells by oxidizing nicotinamide adenine dinucleotide with hydrogen (NADH) to nicotinamide adenine dinucleotide (NAD+). The production of ATP is preferentially inhibited, leading to the malfunction of efflux pumps due to the lack of ATP and making resistant cells more impressionable to anticancer drugs. The in vitro and in vivo experiments confirmed that PCS could induce amplified oxidative stress and efficiently overcome MDR in cancer cells. We believe that the polymer with amplified oxidative stress in cancer cells holds great promise in developing polymer-based drug delivery systems to reverse MDR for cancer therapy.

Dual-locking nanoprobe based on hemicyanine for orthogonal stimuli-triggered precise cancer imaging and therapy.

Currently, stimulus-responsive nanomedicines are usually activated by a single cancer-associated biomarker and utilize different image/therapeutic agents for cancer imaging/therapy, which restricts the specificity of nanomedicine and complicates their design. Herein, we report a novel dual-locking theranostic nanoprobe (DL-P) based on near-infrared (NIR) hemicyanine CyNH2 with two orthogonal stimuli of cancer cell lysosomal pH (first "lock")- and lysosome-overexpressed cathepsin B (CTB, second "lock")-triggered NIR fluorescence turn-on and drug activation to improve the specificity of cancer imaging and therapy. The fluorescence of CyNH2 was initially quenched due to intramolecular charge transfer (ICT) but could be selectively activated under the dual-key stimulation of lysosomal pH and CTB to liberate CyNH2, resulting in strong NIR fluorescence turn-on for cancer imaging. Moreover, CyNH2 caused mitochondrial dysfunction to inhibit cancer cell proliferation in the absence of laser irradiation, which can be used in cancer therapy. Compared with previously reported probes that respond to a single stimulus, this dual-locking nanoprobe that is responsive to two orthogonal stimuli triggers with integrated imaging and therapy function in a single agent exhibits increased selectivity and specificity, which provides a prospective strategy for precise cancer imaging and therapy.

Double exchange interaction promoted high-valence metal sites for neutral oxygen evolution reaction.

A unique double-exchange strategy is adopted to access active high-valent transition metal sites during neutral oxygen evolution reaction (OER). This double-exchange is realized through electronic interaction between transition metal ions and foreign dopants in a transition metal oxide. Based on systematical evaluation on dopants with varied d-electron numbers, we demonstrate that the d electron-poor dopant exhibits more significant double-exchange interaction with the transition metal ions, and therefore obtains more active high-valence metal sites, and thus achieves better neutral OER performance.

Adsorption and visible-light photodegradation of organic dyes with TiO2/conjugated microporous polymer composites.

A series of composite materials made of TiO2 and conjugated microporous polymers (CMPs) were prepared with a hydrothermal method and used as both adsorbents and photocatalysts for the adsorption and visible-light photodegradation of organic dyes in aqueous solutions. It is found that the blending of CMPs can significantly improve both the adsorption capacity and the photocatalytic degradation activity of TiO2 towards organic dyes.