Shine and darkle the blood vessels: Multiparameter hypersensitive MR angiography for diagnosis of panvascular diseases.

Magnetic resonance angiography (MRA) is pivotal for diagnosing panvascular diseases. However, single-modality MRA falls short in diagnosing diverse vascular abnormalities. Thus, contrast agents combining T1 and T2 effects are sought for multiparameter MRA with clinical promise, yet achieving a balance in T1 and T2 contrast enhancement effects remains a scientific challenge. Herein, we developed a hypersensitive multiparameter MRA strategy using dual-modality NaGdF4 nanoparticles. Because of the longer tumbling time (τR), NaGdF4 nanoparticles can improve the longitudinal relaxivity (r1), brightening vessels in T1-weighted sequences. Simultaneously, the regular arrangement of Gd3+ in the crystal induces magnetic anisotropy, creating local static magnetic field heterogeneity and generating negative signals in T2-weighted sequences. Consequently, the efficacy of NaGdF4-enhanced high-resolution multiparameter MRA has been validated in diagnosing ischemic stroke and Alzheimer's disease in rodent models. In addition, the dual-contrast imaging has been realized on swine with a clinical 3.0-T magnetic resonance imaging scanner, highly emphasizing the clinical translation prospect.

A NIR-II Organic Dendrimer with Superb Photothermal Performance Based on Electron-Donor Iteration for Photothermal Immunotherapy.

Organic photothermal materials have attracted extensive attention due to their designable molecular structure, tunable excited-state properties, and excellent biocompatibility, however, the development of near-infrared II (NIR-II) absorbing organic photothermal materials with high photothermal conversion efficiency (PTCE) and molar extinction coefficient (ɛ) remains challenging. Herein, a novel "electron-donor iteration" strategy is proposed to construct organic photothermal dendrimers (CR-DPA-T, CR-(DPA)2-T and CR-(DPA)3-T) with donor-π-acceptor-π-donor (D-π-A-π-D) features and diradical characteristics. Owing to the enhanced D-A effect and intramolecular motions, their absorption and photothermal capacity increase as the generation grows. Surprisingly, an excellent photothermal performance (ɛ1064 × PTCE1064) with a superb value of 2.85 × 104 in the NIR-II region is achieved for CR-(DPA)3-T nanoparticles (CR-(DPA)3-T NPs) compared to most reported counterparts. Besides, CR-(DPA)3-T NPs exhibit superior antitumor efficacy by the synergistic effect of photothermal therapy (PTT) and immunotherapy, efficiently inhibiting the growth of both primary and distant tumors. To the best knowledge, organic photothermal dendrimer is for the first time reported, and a universal donor engineering strategy is offered to develop NIR-II-absorbing organic photothermal materials for photothermal immunotherapy.

Biomimetic Nanosensitizer Potentiates Efficient Glioblastoma Gene-Radiotherapy through Synergistic Hypoxia Mitigation and PLK1 Silencing.

Postoperative radiotherapy currently stands as the cornerstone of glioblastoma (GBM) treatment. Nevertheless, low-dose radiotherapy has been proven ineffective for GBM, due to hypoxia in the GBM microenvironment, which renders the resistance to radiation-induced cell death. Moreover, the overexpression of the PLK1 gene in glioma cells enhances GBM proliferation, invasion, metastasis, and resistance to radiation. This study introduced a hybrid membrane-camouflaged biomimetic lipid nanosensitizer (CNL@miPA), which efficiently encapsulated gold nanoclusters (PA) and miR-593-5p by a chimeric membrane derived from lipids, cancer cells, and natural killer cells. CNL@miPA exhibited exceptional blood-brain barrier and tumor tissue penetration, effectively ameliorating hypoxia and synergizing with radiotherapy. By enabling prolonged miRNA circulation in the bloodstream and achieving high enrichment at the tumor site, CNL@miPA significantly suppressed tumor growth in combination treatment, thereby significantly extending the survival period of treated mice. Overall, the developed biomimetic nanosensitizer represented an efficient and multifunctional targeted delivery system, offering a novel strategy for gene-radiotherapy of GBM.

High-Resolution Magnetic Resonance Angiography of Tumor Vasculatures with an Interlocking Contrast Agent.

The comprehensive evaluation of tumor vasculature that is crucial for the development, expansion, and spread of cancer still remains a great challenge, especially the three-dimensional (3D) evaluation of vasculatures. In this study, we proposed a magnetic resonance (MR) angiography strategy with interlocking stratagem of zwitterionic Gd-chelate contrast agents (PAA-Gd) for continuous monitoring of tumor angiogenesis progression in 3D. Owing to the zwitterionic structure and nanoscale molecular diameter, the longitudinal molar relaxivity (r1) of PAA-Gd was 2.5 times higher than that of individual Gd-chelates on a 7.0 T MRI scanner, resulting in the higher-resolution visualization of tumor vasculatures. More importantly, PAA-Gd has the appropriate blood half-life (69.2 min), emphasizing the extended imaging window compared to the individual Gd-chelates. On this basis, by using PAA-Gd as the contrast agent, the high-resolution, 3D depiction of the spatiotemporal distribution of microvasculature in solid tumors formed by different cell lines over various inoculation times has been obtained. This method offers an effective approach for early tumor diagnosis, development assessment, and prognosis evaluation.

Lignin-Based Nanoparticles for Combination of Tumor Oxidative Stress Amplification and Reactive Oxygen Species Responsive Drug Release.

In this study, maleic anhydride-modified lignin (LG-M), a ROS-cleavable thioketal (TK) bond, and polyethylene glycol (PEG) were used to synthesize a lignin-based copolymer (LG-M(TK)-PEG). Doxorubicin (DOX) was attached to the ROS-cleavable bond in the LG-M(TK)-PEG for the preparation of the ROS-activatable DOX prodrug (LG-M(TK-DOX)-PEG). Nanoparticles (NPs) with a size of 125.7 ± 3.1 nm were prepared by using LG-M(TK-DOX)-PEG, and they exhibited enhanced uptake by cancer cells compared to free DOX. Notably, the presence of lignin in the nanoparticles could boost ROS production in breast cancer 4T1 cells while showing little effect on L929 normal cells. This selective effect facilitated the specific activation of the DOX prodrug in the tumor microenvironment, resulting in the superior tumor inhibitory effects and enhanced biosafety relative to free DOX. This work demonstrates the potential of the LG-M(TK-DOX)-PEG NPs as an efficient drug delivery system for cancer treatment.

Nano-sensitizer with self-amplified drug release and hypoxia normalization properties potentiates efficient chemoradiotherapy of pancreatic cancer.

The hypoxic nature of pancreatic cancer, one of the most lethal malignancies worldwide, significantly impedes the effectiveness of chemoradiotherapy. Although the development of oxygen carriers and hypoxic sensitizers has shown promise in overcoming tumor hypoxia. The heterogeneity of hypoxia-primarily caused by limited oxygen penetration-has posed challenges. In this study, we designed a hypoxia-responsive nano-sensitizer by co-loading tirapazamine (TPZ), KP372-1, and MK-2206 in a metronidazole-modified polymeric vesicle. This nano-sensitizer relies on efficient endogenous NAD(P)H quinone oxidoreductase 1-mediated redox cycling induced by KP372-1, continuously consuming periphery oxygen and achieving evenly distributed hypoxia. Consequently, the normalized tumor microenvironment facilitates the self-amplified release and activation of TPZ without requiring deep penetration. The activated TPZ and metronidazole further sensitize radiotherapy, significantly reducing the radiation dose needed for extensive cell damage. Additionally, the coloaded MK-2206 complements inhibition of therapeutic resistance caused by Akt activation, synergistically enhancing the hypoxic chemoradiotherapy. This successful hypoxia normalization strategy not only overcomes hypoxia resistance in pancreatic cancer but also provides a potential universal approach to sensitize hypoxic tumor chemoradiotherapy by reshaping the hypoxic distribution.

Biodegradable MXene Quantum Dots with High Near-Infrared Photothermal Performance for Cancer Treatment.

Photothermal therapy (PTT) offers significant potential in cancer treatment due to its short, simple, and less harmful nature. However, obtaining a photothermal agent (PTA) with good photothermal performance and biocompatibility remains a challenge. MXenes, which are PTAs, have shown promising results in cancer treatment. This study presents the preparation of Ti3C2 MXene quantum dots (MXene QDs) using a simple hydrothermal and ultrasonic method and their use as a PTA for cancer treatment. Compared to conventional MXene QDs synthesized using only the hydrothermal method, the ultrasonic process increased the degree of oxidation on the surface of the MXene QDs. This resulted in the presence of more hydrophilic groups such as hydroxyl groups on the MXene QD surfaces, leading to excellent dispersion in the aqueous system and biocompatibility of the prepared MXene QDs without the need for surface modification. The MXene QDs showed great photothermal performance with a photothermal conversion efficiency of 62.5%, resulting in the highest photothermal conversion efficiency among similar materials reported thus far. Both in vitro and in vivo experiments have proved the potent tumor inhibitory effect of the MXene QD-mediated PTT, with minimal harm to mice. Therefore, these MXene QDs hold a significant promise for clinical applications.

STING Membrane Prevents Post-Surgery Tissue Adhesion and Tumor Recurrence of Colorectal Cancer.

Surgery is the standard treatment regimen for resectable colorectal cancer (CRC). However, it is very hard to completely remove all cancer cells in clinical practice, leading to the high recurrence rates of the disease. Moreover, the post-surgery tissue adhesion greatly prevents the possibility of reoperation, significantly limiting the long-term surviving of CRC patients. To overcome CRC recurrence and avoid the post-surgery tissue adhesion, this work develops a novel stimulator of interferon genes "STING" membrane based on the coaxial electrospinning technology and hyaluronic acid modification. A reactive oxygen species responsive prodrug of gambogic acid (GB) and a potent STING agonist (CDN) are coloaded in the core-shell structure of the membrane, which endows the loaded drug with sustained and sequential release patterns. The localized delivery of GB and CDN can selectively induce efficient immunogenic cell death of cancer cells and then evoke the systemic anticancer immunity by activating the Cyclic GMP-AMP (cGAMP) synthase/STING pathway. As-designed "STING" membrane not only safely prevents tumor recurrence through the synergistic chemoimmunotherapy but also efficiently avoids the post-surgery tissue adhesion, facilitating the clinical intervention of CRC.

Novel Heterogeneous Hydrogel with Dual-Responsive Shape Programmability and Good Biocompatibility.

Shape memory polymers (SMPs) responsive to various external stimuli can realize a complex shape transformation process and have attracted extensive attention. However, integrating multiple stimulus-responsive mechanisms in one material often requires a complex molecular design and synthesis procedure. In this work, we designed a novel dual-responsive heterogeneous hydrogel (PU-PAM/Alg/PDA), which was manufactured through in situ free radical polymerization of acrylamide (AM) in the presence of alginate (Alg) and polydopamine (PDA) in a porous polycaprolactone-based polyurethane foam (PU-foam). The PU-PAM/Alg/PDA hydrogel could achieve thermal responsiveness through melting-crystallization transformation of polycaprolactone (PCL), while the metallo-supramolecular interactions between Alg and Fe3+ could provide ion responsiveness for this hydrogel. This dual-programmable feature endowed the heterogeneous hydrogel with a complex shape-morphing behavior and also a reconfiguration ability for the permanent shape. Meanwhile, the strong hydrogen bondings between PDA and polyurethane chains enhanced the interfacial adhesions, resulting in the structural integrity and excellent mechanical property of PU-PAM/Alg/PDA. The in vitro and in vivo tests revealed the good biocompatibility of the heterogeneous hydrogel, and the potential of the heterogeneous hydrogel as an esophageal stent was evaluated in vitro as conceptual proof.

Photodynamic Therapy Derived Personalized Whole Cell Tumor Vaccine Prevents Postsurgery Tumor Recurrence and Metastasis.

In order to avoid the time-consuming and laborious identification of tumor-specific antigens (TSAs) during the traditional vaccine fabrication process, a versatile photodynamic therapy (PDT)-based method is developed to construct a whole-tumor antigen tumor vaccine (TV) from surgically resected tumor tissues for personalized immunotherapy. Mucoadhesive nanoparticles containing small-molecular photosensitizer are fabricated and directly co-incubated with suspended tumor cells obtained after cytoreduction surgery. After irradiation with a 405 nm laser, potent immunogenic cell death of cancer cells could be induced. Along with the release of TSAs, the as-prepared TV could activate safe and robust tumor-specific immune responses, leading to efficient suppression of postsurgery tumor recurrence and metastasis. The as-prepared TV cannot only be applied alone through various administration routes but also synergize with immunoadjuvant, chemotherapeutics, and immune checkpoint blockers to exert more potent immune responses. This work provides an alternative way to promote the clinical translation of PDT, which is generally restricted by the limited penetration of light. Moreover, the versatile strategy of vaccine fabrication also facilitates the clinical application of personalized whole-cell tumor vaccines.

Hypersensitive MR angiography based on interlocking stratagem for diagnosis of cardiac-cerebral vascular diseases.

Magnetic resonance (MR) angiography is one of the main diagnostic approaches for cardiac-cerebral vascular diseases. Nevertheless, the non-contrast-enhanced MR angiography suffers from its intrinsic problems derived from the blood flow-dependency, while the clinical Gd-chelating contrast agents are limited by their rapid vascular extravasation. Herein, we report a hypersensitive MR angiography strategy based on interlocking stratagem of zwitterionic Gd-chelate contrast agents (PAA-Gd). The longitudinal molar relaxivity of PAA-Gd was 4.6-times higher than that of individual Gd-chelates as well as appropriate blood half-life (73.8 min) and low immunogenicity, enabling sophisticated micro-vessels angiography with a resolution at the order of hundred micrometers. A series of animal models of cardiac-cerebrovascular diseases have been built for imaging studies on a 7.0 T MRI scanner, while the clinical translation potential of PAA-Gd has been evaluated on swine on a 3.0 T clinical MRI scanner. The current studies offer a promising strategy for precise diagnosis of vascular diseases.

Cell membrane-based nanomaterials for theranostics of central nervous system diseases.

Central nervous system (CNS) diseases have been widely acknowledged as one of the major healthy concerns globally, which lead to serious impacts on human health. There will be about 135 million CNS diseases cases worldwide by mid-century, and CNS diseases will become the second leading cause of death after the cardiovascular disease by 2040. Most CNS diseases lack of effective diagnostic and therapeutic strategies with one of the reasons that the biological barrier extremely hampers the delivery of theranostic agents. In recent years, nanotechnology-based drug delivery is a quite promising way for CNS diseases due to excellent properties. Among them, cell membrane-based nanomaterials with natural bio-surface, high biocompatibility and biosafety, are of great significance in both the diagnosis and treatment of different CNS diseases. In this review, the state of art of the fabrication of cell membranes-based nanomaterials is introduced. The characteristics of different CNS diseases, and the application of cell membranes-based nanomaterials in the theranostics are summarized. In addition, the future prospects and limitations of cell membrane nanotechnology are anticipated. Through summarizing the state of art of the fabrication, giving examples of CNS diseases, and highlighting the applications in theranostics, the current review provides designing methods and ideas for subsequent cell membrane nanomaterials.

Numerical simulation and exergy analysis of a single-stage GM cryocooler.

Improving the efficiency of the GM cryocoolers is of great importance for energy saving and CO2 emission reduction due to the large amount of cryocoolers installed in the emerging fields of semiconductor manufacture and High Temperature Superconductors (HTS) cooling. Previous studies mainly focused on the losses analysis and optimization on the part of cold head, but the details of losses distribution in the parts of compressor and rotary valve were seldom carried out. In this paper, a numerical model of a single stage GM cryocooler including compressor, rotary valve and expander is built, and the feasibility of the model is verified by the experimental results. The losses characteristics of the whole cryocooler are studied based on the exergy analysis method with the help of the numerical model. The results indicate that the main losses are occurred in compressor and rotary valve, the value of exergy loss in compressor decrease with the cooling temperature, and accounts for more than 60% at all cooling temperature. The loss in rotary valve accounts for about 20% of the input electric power, and it does not significantly vary at different cooling temperatures. Pressure drop dominates the loss in the compressor and rotary valve. The insufficient heat exchange between the working gas and regenerative material is the main loss in regenerator, and the losses in regenerator increase significantly with the decrease of cooling temperature when the compressor and rotary valve are fixed. This study provides useful guides for the optimization of GM-type cryocoolers.

Oncogene-targeting nanoprobes for early imaging detection of tumor.

Malignant tumors have been one of the major reasons for deaths worldwide. Timely and accurate diagnosis as well as effective intervention of tumors play an essential role in the survival of patients. Genomic instability is the important foundation and feature of cancer, hence, in vivo oncogene imaging based on novel probes provides a valuable tool for the diagnosis of cancer at early-stage. However, the in vivo oncogene imaging is confronted with great challenge, due to the extremely low copies of oncogene in tumor cells. By combining with various novel activatable probes, the molecular imaging technologies provide a feasible approach to visualize oncogene in situ, and realize accurate treatment of tumor. This review aims to declare the design of nanoprobes responded to tumor associated DNA or RNA, and summarize their applications in detection and bioimaging for tumors. The significant challenges and prospective of oncogene-targeting nanoprobes towards tumors diagnosis are revealed as well.

Nanoprobe Based on Biominerals in Protein Corona for Dual-Modality MR Imaging and Therapy of Tumors.

Various functional nanomaterials have been fabricated as diagnostic and therapeutic nanomedicines; however, the nanoparticles closely interact with proteins when immersed in biological fluids, forming a "protein corona" that critically alters the biological identity of nanomedicine. Here, we developed a robust strategy to construct theranostic nanoprobes based on protein-corona-coated Fe3O4 nanoparticles and biomineralization in the corona. Water-soluble carboxylic Fe3O4 nanoparticles were prepared by treating oleate-capped Fe3O4 nanoparticles with Lemieux-von Rudloff reagent. Bovine serum albumin (BSA) was used as a model protein to form a corona on the surface of Fe3O4 nanoparticles, endowing the Fe3O4 nanoparticles with biocompatibility and nonimmunogenicity. The protein corona also provides a template for biomimetic mineralization of Fe3+ with tannic acid (TA) to construct Fe3O4@BSA-TAFeIII nanoprobes. The TA-Fe(III) biominerals can not only act as photothermal therapy agents but also interact with unsaturated transferrin in plasma to form a "hybrid" corona, enabling the nanoprobes to target tumor cells through the mediation of transferrin receptors, which commonly overexpress on tumor cell membranes. Once taken in by tumor cells, the protonation of phenol hydroxyl groups in acidic lysosomes would lead to the release of Fe3+, inducing tumor cell death through a ferroptosis/apoptosis hybrid pathway. In addition, the released Fe3+ can boost the T1-weighted MR imaging performance, and the Fe3O4 nanoparticles serve as T2-weighted MR imaging contrast agents. It is thus believed that the current nanoprobes can realize the enhanced dual-modality MR imaging and combined therapy of tumors through controlling the protein corona and biomineralization.

Prodrug Nanosensitizer Overcomes the Radiation Resistance of Hypoxic Tumor.

Clinical radiation therapy (RT) is often hindered by the low radiation energy absorption coefficient and the hypoxic features of tumor tissues. Among the tremendous efforts devoted to overcoming the barriers to efficient RT, the application of hypoxic radiosensitizers and cell-cycle-specific chemotherapeutics has shown great potential. However, their effectiveness is often compromised by their limited bioavailability, especially in the hypoxic region, which plays a major role in radioresistance. Herein, to simultaneously improve the delivery efficacy of both hypoxic radiosensitizer and cell-cycle-specific drug, a gambogic acid (GA) metronidazole (MN) prodrug (GM) was designed and synthesized based on GA, a naturally occurring chemotherapeutic and multiple pathway inhibitor, and MN, a typical hypoxic radiosensitizer. In combination with MN-containing block copolymers, the prodrug nanosensitizer (NS) of GM was obtained. Owing to the bioreduction of MN, the as-designed prodrug could be efficiently delivered to hypoxic cells and act on mitochondria to cause the accumulation of reactive oxygen species. The strong G2/M phase arrest caused by the prodrug NS could further sensitize treated cells to external radiation under hypoxic conditions by increasing DNA damage and delaying DNA repair. After coadministration of the NS with a well-established tissue-penetrating peptide, efficient tumor accumulation, deep tumor penetration, and highly potent chemoradiotherapy could be achieved.

Poly(ε-Caprolactone) Substrates with Micro/Nanohierarchical Patterned Structures for Cell Culture.

A simple, efficient and controllable one-step template method is proposed to fabricate poly(ε-caprolactone) substrates with micro/nanohierarchical patterned structures. Two kinds of geometric patterns with and without nanowires, i.e., hexagonal and strip with controllable island size and spacing are designed and fabricated. Furthermore, the influence of geometric patterns, island size, island spacing, and patterned nanowires (pNW) on the growth behavior of MG-63 cells is studied in terms of cell density, distribution, proliferation, morphogenesis, and cellular alignment. It is found that MG-63 cells prefer to adhere and grow on the substrate with smaller island size or spacing. Moreover, unlike the hexagonal structure, the strip structure can guide cellular alignment on its surface. In addition, the microisland structures and the pNW play different roles in promoting cell proliferation, distribution, and morphogenesis. It is concluded that the growth behavior of MG-63 cells can be well controlled by precisely adjusting the micro/nanostructure of the substrate surface. A simple and effective method is provided here for the regulation of cell growth behavior.

An inflammation-targeted nanoparticle with bacteria forced release of polymyxin B for pneumonia therapy.

The epidemic of multidrug-resistant Gram-negative bacteria is an ever-growing global concern. Polymyxin B (PMB), a kind of "old fashioned" antibiotic, has been revived in clinical practice and mainly used as last-line antibiotics for otherwise untreatable serious infections because the incidence of the resistance to PMB is currently relatively low in comparison with other antibiotics in vivo owing to the unique bactericidal mechanism of PMB. However, serious adverse side effects, including nephrotoxicity and neurotoxicity, hamper its clinical application. Herein, we describe the development of a nanoparticle that can target sites of inflammation and forcedly release PMB specifically in the area of Gram-negative bacteria. This particle was constructed through the electrostatic self-assembly of hyaluronic acid (HA) and PMB molecules in order to realize the safe and effective treatment of pneumonia. After systemic administration, PMB-HA nanoparticles were found to actively accumulate in the lungs, precisely target the CD44 receptors over-expressed on the membrane of activated endothelial cells in inflammatory sites, and then come into contact with the bacteria resident in the damaged alveolar-capillary membrane. Due to the electrostatic and hydrophobic interactions between PMB and the lipopolysaccharide (LPS) in the outer membranes of bacteria, the PMB molecules in the PMB-HA nanoparticles are expected to escape from the nanoparticles to insert into the bacteria via competitive binding with LPS. Through shielding the cationic nature of PMB, PMB-HA nanoparticles also possess outstanding biosafety performance in comparison to free PMB. It is thus believed that this smart delivery system may pave a new way for the resurrection of PMB in the future clinical treatment of bacterial inflammatory diseases.

Deep-Penetrating Triple-Responsive Prodrug Nanosensitizer Actuates Efficient Chemoradiotherapy in Pancreatic Ductal Adenocarcinoma Models.

Chemoradiotherapy (CRT) is the most accepted treatment for locally advanced pancreatic ductal adenocarcinoma (PDAC) and can significantly improve the R0 resection rate. However, there are few long-term survivors after CRT. Although some polymer nanoparticles have shown potential in alleviating the dose-limiting toxicity and assisting the chemotherapy of PDAC, there are few efficient nanosensitizers (NS) available for CRT of this malignancy, especially in the context of its hypoxic nature. Herein, based on the biological features of PDAC, a γ-glutamyl transpeptidase (GGT)/glutathione (GSH)/hypoxia triple-responsive prodrug NS to overcome the biological barrier and microenvironmental limitations confronted by CRT in PDAC is developed. Due to triple-responsiveness, deep tumor penetration, GSH/hypoxia-responsive drug release/activation, and hypoxia-induced chemoradio-sensitization can be simultaneously achieved with this NS. As a result, tumor shrinkage after CRT with this NS can be observed in both subcutaneous and orthotopic PDAC models, foreshadowing its potential in clinical neoadjuvant CRT.

Bladder cancer selective chemotherapy with potent NQO1 substrate co-loaded prodrug nanoparticles.

Currently, clinical intravesical instillation chemotherapy has been greatly compromised by the toxicological and physiological factors. New formulations that can specifically and efficiently kill bladder cancer cells are in urgent need to overcome the low residence efficiency and dose limiting toxicity of current ones. The combination of mucoadhesive nanocarriers and cancer cell selective prodrugs can to great extent address these limitations. However, the insignificant endogenous stimulus difference between cancer cells and normal cells in most cases and the high local drug concentration make it essential to develop new drugs with broader selectivity-window. Herein, based on the statistically different NQO1 expression between cancerous and normal bladder tissues, the reactive oxygen species (ROS) activatable epirubicin prodrug and highly potent NQO1 substrate, KP372-1, was co-delivered using a GSH-responsive mucoadhesive nanocarrier. After endocytosis, epirubicin could be promptly activated by the NQO1-dependent ROS production caused by KP372-1, thus specifically inhibiting the proliferation of bladder cancer cells. Since KP372-1 is much more potent than some commonly used NQO1 substrates, for example, ß-lapachone, the cascade drug activation could occur under much lower drug concentration, thus greatly lowering the toxicity in normal cells and broadening the selectivity-window during intravesical bladder cancer chemotherapy.