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The combination of chemotherapy and photodynamic therapy (PDT) has promising potential in the synergistic treatment of cancer. However, chemotherapy and photodynamic synergistic therapy are impeded by uncontrolled chemotherapeutics release behavior, targeting deficiencies, and hypoxia‐associated poor PDT efficacy in solid tumors. Here, a platinum nanozyme (PtNP) loaded reactive oxygen species (ROS)‐responsive prodrug nanoparticle (CPT‐TK‐HPPH/Pt NP) is created to overcome these limitations. The ROS‐responsive prodrug consists of a thioketal bond linked with camptothecin (CPT) and photosensitizer‐2‐(1‐hexyloxyethyl)‐2‐devinyl pyropheophorbide‐a (HPPH). The PtNP in CPT‐TK‐HPPH/Pt NP can efficiently catalyze the decomposition of hydrogen peroxide (H2O2) into oxygen to relieve hypoxia. The production of oxygen can satisfy the consumption of HPPH under 660 nm laser irradiation to attain the on‐demand release of CPT and ensure enhanced photodynamic therapy. As a tumor diagnosis agent, the results of photoacoustic imaging and fluorescence imaging for CPT‐TK‐HPPH/Pt NP exhibit desirable long circulation and enhanced in vivo targeting. CPT‐TK‐HPPH/Pt NPs effectively inhibit tumor proliferation and growth in vitro and in vivo. CPT‐TK‐HPPH/Pt NP, with its excellent ROS‐responsive drug release behavior and enhanced PDT efficiency can serve as a new cancer theranostic agent, and will further promote the research of chemophotodynamic synergistic cancer therapy. The platinum nanozyme (PtNP) loaded reactive oxygen species‐responsive prodrug nanoparticle (CPT‐TK‐HPPH/Pt NP) which could achieve the “on‐demand” release of CPT and relieve hypoxia to enhance photodynamic therapy efficiency, exhibits desirable long circulation and effectively inhibits tumor proliferation and growth in vitro and in vivo, has great promising potential in chemophotodynamic synergistic cancer therapy.

Cuproptosis is an emerging cell death pathway that depends on the intracellular Cu ions. Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and trigger cuproptosis. However, ES can be rapidly removed and metabolized during intravenous administration, leading to a short half‐life and limited tumor accumulation, which hampers its clinical application. Here, the study develops a reactive oxygen species (ROS)‐responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG) to encapsulate ES‐Cu compound (EC), forming ECPCP. ECPCP significantly prolongs the systemic circulation of EC and enhances its tumor accumulation. After cellular internalization, the PCP coating stimulatingly dissociates exposing to the high‐level ROS, and releases ES and Cu, thereby triggering cell death via cuproptosis. Meanwhile, Cu2+‐stimulated Fenton‐like reaction together with CA‐stimulated ROS production simultaneously breaks the redox homeostasis, which compensates for the insufficient oxidative stress treated with ES alone, in turn inducing immunogenic cell death of tumor cells, achieving simultaneous cuproptosis and immunotherapy. Furthermore, the excessive ROS accelerates the stimuli‐dissociation of ECPCP, forming a positive feedback therapy loop against tumor self‐alleviation. Therefore, ECPCP as a nanoplatform for cuproptosis and immunotherapy improves the dual antitumor mechanism of ES and provides a potential optimization for ES clinical application. In this study, a self‐ampslifying ROS‐responsive nanoplatform (ECPCP) is developed, of which a polymer based on cinnamaldehyde and polyethylene glycol is fabricated to encapsulate elesclomol‐Cu compound. ECPCP successfully prolongs the systemic circulation of elesclomol and enhances its tumor accumulation, subsequently improving the dual antitumor mechanism of ES, cuproptosis, and immunotherapy, and provides a potential optimization for ES clinical application.

Retinal ischemia–reperfusion (RIR) injury is involved in the pathogenesis of various vision‐threatening diseases. The overproduction of reactive oxygen species (ROS) is thought to be the main cause of RIR injury. A variety of natural products, including quercetin (Que), exhibit potent antioxidant activity. However, the lack of an efficient delivery system for hydrophobic Que and the presence of various intraocular barriers limit the effective retinal delivery of Que in clinical settings. In this study, we encapsulated Que into ROS‐responsive mitochondria‐targeted liposomes (abbreviated to Que@TPP‐ROS‐Lips) to achieve the sustained delivery of Que to the retina. The intracellular uptake, lysosome escape ability, and mitochondria targeting ability of Que@TPP‐ROS‐Lips were evaluated in R28 retinal cells. Treating R28 cells with Que@TPP‐ROS‐Lips significantly ameliorated the decrease in ATP content, ROS generation, and increase in the release of lactate dehydrogenase in an in vitro oxygen–glucose deprivation (OGD) model of retinal ischemia. In a rat model, the intravitreal injection of Que@TPP‐ROS‐Lips 24 h after inducing retinal ischemia significantly enhanced retinal electrophysiological recovery and reduced neuroinflammation, oxidative stress, and apoptosis. Que@TPP‐ROS‐Lips were taken up by retina for at least 14 days after intravitreal administration. Molecular docking and functional biological experiments revealed that Que targets FOXO3A to inhibit oxidative stress and inflammation. Que@TPP‐ROS‐Lips also partially inhibited the p38 MAPK signaling pathway, which contributes to oxidative stress and inflammation. In conclusion, our new platform for ROS‐responsive and mitochondria‐targeted drug release shows promise for the treatment of RIR injury and promotes the clinical application of hydrophobic natural products.

The scarcity of effective neuroprotective agents and the presence of blood‐brain barrier (BBB)‐mediated extremely inefficient intracerebral drug delivery are predominant obstacles to the treatment of cerebral ischemic stroke (CIS). Herein, ROS‐responsive borneol‐based amphiphilic polymeric NPs are constructed by using traditional Chinese medicine borneol as functional blocks that served as surface brain‐targeting ligand, inner hydrophobic core for efficient drug loading of membrane‐permeable calcium chelator BAPTA‐AM, and neuroprotective structural component. In MCAO mice, the nanoformulation (polymer: 3.2 mg·kg−1, BAPTA‐AM: 400 µg·kg−1) reversibly opened the BBB and achieved high brain biodistribution up to 12.7%ID/g of the total administered dose after 3 h post single injection, effectively restoring intracellular Ca2+ and redox homeostasis, improving cerebral histopathology, and inhibiting mitochondrial PI3K/Akt/Bcl‐2/Bax/Cyto‐C/Caspase‐3,9 apoptosis pathway for rescuing dying neurons (reduced apoptosis cell from 59.5% to 7.9%). It also remodeled the inflammatory microenvironment in cerebral ischemic penumbra by inhibiting astrocyte over‐activation, reprogramming microglia polarization toward an anti‐inflammatory phenotype, and blocking NF‐κB/TNF‐α/IL‐6 signaling pathways. These interventions eventually reduced the cerebral infarction area by 96.3%, significantly improved neurological function, and restored blood flow reperfusion from 66.2% to ≈100%, all while facilitating BBB repair and avoiding brain edema. This provides a potentially effective multiple‐stage sequential treatment strategy for clinical CIS. Traditional Chinese medicine borneol as brain‐targeted and therapeutic functional blocks of ROS‐responsive polymeric NPs. The responsively released calcium chelator BAPTA‐AM effectively inhibit Ca2+ overload in injured neurons. Dissociated borneol synergistically restore redox homeostasis, inhibit inflammatory cascade and promote BBB repair. This formulation promotes multiple‐stage sequential treatment strategy in ischemic stroke.

Acute kidney injury (AKI) caused by sepsis is a serious disease which mitochondrial oxidative stress and inflammatory play a key role in its pathophysiology. Ceria nanoparticles hold strong and recyclable reactive oxygen species (ROS)-scavenging activity, have been applied to treat ROS-related diseases. However, ceria nanoparticles can't selectively target mitochondria and the ultra-small ceria nanoparticles are easily agglomerated. To overcome these shortcomings and improve therapeutic efficiency, we designed an ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury. : Ceria nanoparticles were modified with triphenylphosphine (TCeria NPs), followed by coating with ROS-responsive organic polymer (mPEG-TK-PLGA) and loaded atorvastatin (Atv/PTP-TCeria NPs). The physicochemical properties, drug release profiles, mitochondria-targeting ability, antioxidant, anti-apoptotic activity and treatment efficacy of Atv/PTP-TCeria NPs were examined. : Atv/PTP-TCeria NPs could accumulate in kidneys and hold a great ability to ROS-responsively release drug and TCeria NPs could target mitochondria to eliminate excessive ROS. study suggested Atv/PTP-TCeria NPs exhibited superior antioxidant and anti-apoptotic activity. study showed that Atv/PTP-TCeria NPs effectively decreased oxidative stress and inflammatory, could protect the mitochondrial structure, reduced apoptosis of tubular cell and tubular necrosis in the sepsis-induced AKI mice model. This ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin has favorable potentials in the sepsis-induced AKI therapy.

The synergistic combination of chemotherapy and photodynamic therapy has attracted considerable attention for its enhanced antitumoral effects; however, it remains challenging to successfully delivery photosensitizers and anticancer drugs while minimizing drug leakage at off‐target sites. A red‐light‐activatable metallopolymer, Poly(Ru/PTX), is synthesized for combined chemo‐photodynamic therapy. The polymer has a biodegradable backbone that contains a photosensitizer Ru complex and the anticancer drug paclitaxel (PTX) via a singlet oxygen (1O2) cleavable linker. The polymer self‐assembles into nanoparticles, which can efficiently accumulate at the tumor sites during blood circulation. The distribution of the therapeutic agents is synchronized because the Ru complex and PTX are covalently conjugate to the polymer, and off‐target toxicity during circulation is also mostly avoided. Red light irradiation at the tumor directly cleaves the Ru complex and produces 1O2 for photodynamic therapy. Sequentially, the generated 1O2 triggers the breakage of the linker to release the PTX for chemotherapy. Therefore, this novel sequential dual‐model release strategy creates a synergistic chemo‐photodynamic therapy while minimizing drug leakage. This study offers a new platform to develop smart delivery systems for the on‐demand release of therapeutic agents in vivo. Amphiphilic metallopolymers, which have a biodegradable polycarbonate backbone that contains the photosensitizer Ru complex and the anticancer drug paclitaxel (PTX) via a singlet oxygen cleavable linker, self‐assemble into nanoparticles. The nanoparticles carry the therapeutic agents into tumor cells without drug leakage. Red light irradiation induces sequential release of the Ru complex and PTX for enhanced chemo‐photodynamic therapy.

PD‐1/PD‐L1 inhibitors have emerged as standard treatments for advanced solid tumors; however, challenges such as a low overall response rate and systemic side effects impede their implementation. Hypoxia drives the remodeling of the tumor microenvironment, which is a leading reason for the failure of immunotherapies. Despite some reported strategies to alleviate hypoxia, their individual limitations constrain further improvements. Herein, a novel two‐pronged strategy is presented to efficiently address hypoxia by simultaneously adopting atovaquone (ATO, inhibiting oxygen consumption) and oxyhemoglobin (HbO2, directly supplementing oxygen) within a multifunctional aggregate termed NPs‐aPD‐1/HbO2/ATO. In addition to eliminating hypoxia with these two components, this smart aggregate also includes albumin and an ROS‐responsive cross‐linker as a controlled release scaffold, along with PD‐1 antibody (aPD‐1) for immunotherapy. Intriguingly, NPs‐aPD‐1/HbO2/ATO demonstrates exceptional tumor targeting in vivo, exhibiting ≈4.2 fold higher accumulation in tumors than in the liver. Consequently, this aggregate not only effectively mitigates hypoxia and significantly assists aPD‐1 immunotherapy but also simultaneously resolves the targeting and systemic toxicity issues associated with individual administration of each component. This study proposes substantial implications for drug‐targeted delivery, addressing tumor hypoxia and advancing immunotherapy, providing valuable insights for advancing cancer treatment strategies. Here, a smart aggregate (NPs‐aPD‐1/HbO2/ATO) comprised of PD‐1 antibody (aPD‐1), hemoglobin (Hb), atovaquone (ATO) and an ROS‐responsive cross‐linker is presented. Tumor ROS disrupts the linkers, releasing Hb and ATO to alleviate hypoxia via an open‐source and reduce‐expenditure strategy, respectively, and assisting the released aPD‐1 to fight against the cancer. This approach overcomes the side effects of systemic administration of the components and profoundly advances cancer immunotherapy.

Reactive oxygen species (ROS)-sensitive drug delivery systems (DDS) specifically responding to altered levels of ROS in the pathological microenvironment have emerged as an effective means to enhance the pharmaceutical efficacy of conventional nanomedicines, while simultaneously reducing side effects. In particular, the use of the biocompatible, biodegradable, and non-toxic ROS-responsive thioketal (TK) functional group in the design of smart DDS has grown exponentially in recent years. In the design of TK-based DDS, different technological uses of TK have been proposed to overcome the major limitations of conventional DDS counterparts including uncontrolled drug release and off-target effects. This review will focus on the different technological uses of TK-based biomaterials in smart nanomedicines by using it as a linker to connect a drug on the surface of nanoparticles, form prodrugs, as a core component of the DDS to directly control its structure, to control the opening of drug-releasing gates or to change the conformation of the nano-systems. A comprehensive view of the various uses of TK may allow researchers to exploit this reactive linker more consciously while designing nanomedicines to be more effective with improved disease-targeting ability, providing novel therapeutic opportunities in the treatment of many diseases.

Lung transplantation (LTx) is a life‐saving procedure for patients with end‐stage respiratory failure; however, primary graft dysfunction (PGD), primarily induced by ischemia/reperfusion injury (IRI), remains a major complication. Although ex vivo lung perfusion (EVLP) improves preservation, clinical translation remains challenging owing to IRI complexity. Here, a novel approach is presented to mitigate lung IRI by developing of neutrophil‐derived ROS‐responsive cellular vesicles (SOD2‐Fer‐1@CVs). This hybrid system integrates superoxide dismutase 2 (SOD2)‐overexpressing neutrophil nanovesicles with ROS‐responsive liposomes loaded with ferrostatin‐1 (Fer‐1), a potent ferroptosis inhibitor. SOD2‐Fer‐1@CVs enabled targeted delivery to inflamed tissues and high oxidative stress environments, enabling ROS‐triggered release of SOD2 and Fer‐1. The SOD2‐Fer‐1@CVs system mechanistically targeted the core pathological pathways of IRI, including oxidative stress alleviation, adsorption and neutralization of pro‐inflammatory cytokines, ferroptosis suppression, and restoration of endothelial barrier integrity, with concurrent promotion of macrophage M2 polarization. Using the proprietary small‐animal EVLP platform, the therapeutic administration of SOD2‐Fer‐1@CVs significantly mitigated of reperfusion‐related pathologies and improved graft performance, including enhanced oxygenation, reduced airway resistance, and restored lung compliance, attenuating lung injury after LTx. This study established a novel nanotherapeutic strategy that synergizes with EVLP to address multifactorial IRI, showing high translational potential for improving donor lung quality and LTx outcomes. Engineered neutrophil‐derived vesicles (SOD2‐Fer‐1@CVs) co‐delivering antioxidant and ferroptosis‐inhibitory agents enable inflammation‐targeted, ROS‐responsive therapy for ischemia–reperfusion injury in lung transplantation. Synergizing with ex vivo lung perfusion, this strategy alleviates oxidative stress and inflammation, restores vascular integrity, and improves graft function, offering translational potential for enhancing lung transplant outcomes.

Precise and effective management of myocardial ischemia/reperfusion injury (MIRI) is still a formidable challenge in clinical practice. Additionally, real‐time monitoring of drug aggregation in the MIRI region remains an open question. Herein, a drug delivery system, hesperadin and ICG assembled in PLGA‐Se‐Se‐PEG‐IMTP (HI@PSeP‐IMTP), is designed to deliver hesperadin and ICG to the MIRI region for in vivo optical imaging tracking and to ameliorate MIRI. The peak aggregation of nanoprobes in the MIRI region is monitored by near‐infrared fluorescence and photoacoustic imaging. The maximal fluorescence and photoacoustic signals of the HI@PSeP‐IMTP group in the MIRI region rise ≈32% and 40% respectively compared with that of HI@PSeP group. Moreover, HI@PSeP‐IMTP effectively mitigates MIRI due to a synergistic integration of diselenide bonds and hesperadin, which can eliminate ROS and suppress cardiac inflammation. Specifically, the expression levels of p‐CaMKII, p‐IκBα, and p65 in the MIRI region in the HI@PSeP‐IMTP group demonstrate a reduction of 30%, 46%, and 42% respectively compared to that of the PBS group. Collectively, HI@PSeP‐IMTP provides new insights into the development of drugs integrating diagnosis and treatment for MIRI. Myocardial ischemia/reperfusion injury (MIRI) seriously threatens human life, and the corresponding monitoring and treatment require improvement. HI@PSeP‐IMTP, a highly biocompatible probe with advanced self‐monitoring capabilities, enables precise detection of ischemic area distribution and drug release via photoacoustic and fluorescence imaging. This study offers a comprehensive understanding of the probe behavior and efficacy, and shows great potential in alleviating MIRI.