Critical learning from industrial catalysis for nanocatalytic medicine.

Systematical and critical learning from industrial catalysis will bring inspiration for emerging nanocatalytic medicine, but the relevant knowledge is quite limited so far. In this review, we briefly summarize representative catalytic reactions and corresponding catalysts in industry, and then distinguish the similarities and differences in catalytic reactions between industrial and medical applications in support of critical learning, deep understanding, and rational designing of appropriate catalysts and catalytic reactions for various medical applications. Finally, we summarize/outlook the present and potential translation from industrial catalysis to nanocatalytic medicine. This review is expected to display a clear picture of nanocatalytic medicine evolution.

Harnessing inhaled nanoparticles to overcome the pulmonary barrier for respiratory disease therapy.

The lack of effective treatments for pulmonary diseases presents a significant global health burden, primarily due to the challenges posed by the pulmonary barrier that hinders drug delivery to the lungs. Inhaled nanomedicines, with their capacity for localized and precise drug delivery to specific pulmonary pathologies through the respiratory route, hold tremendous promise as a solution to these challenges. Nevertheless, the realization of efficient and safe pulmonary drug delivery remains fraught with multifaceted challenges. This review summarizes the delivery barriers associated with major pulmonary diseases, the physicochemical properties and drug formulations affecting these barriers, and emphasizes the design advantages and functional integration of nanomedicine in overcoming pulmonary barriers for efficient and safe local drug delivery. The review also deliberates on established nanocarriers and explores drug formulation strategies rooted in these nanocarriers, thereby furnishing essential guidance for the rational design and implementation of pulmonary nanotherapeutics. Finally, this review cast a forward-looking perspective, contemplating the clinical prospects and challenges inherent in the application of inhaled nanomedicines for respiratory diseases.

Ultrasound-Driven Piezoelectrocatalytic Immunoactivation of Deep Tumor.

Tumor heterogeneity makes routine drugs difficult to penetrate solid tumors, limiting their therapy efficacies. Based on high tissue penetrability of hydrogen molecules (H2 ) and ultrasound (US) and the immunomodulation effects of H2 and lactic acid (LA), this work proposes a novel strategy of US-driven piezoelectrocatalytic tumor immunoactivation for high-efficacy therapy of deep tumors by piezoelectrocatalytic hydrogen generation and LA deprivation. A kind of US-responsive piezoelectric SnS nanosheets (SSN) is developed to realize US-triggered local hydrogen production and simultaneous LA deprivation in deep tumors. The proof-of-concept experiments which are executed on an orthotopic liver cancer model have verified that intratumoral SSN-medicated piezoelectrocatalytically generated H2 liberates effector CD8+ T cells from the immunosuppression of tumor cells through down-regulating PD-L1 over-expression, and simultaneous LA deprivation activates CD8+ T cells by inhibiting regulatory T cells, efficiently co-activating tumor immunity and achieving a high outcome of liver tumor therapy with complete tumor eradication and 100% mice survival. The proposed strategy of US-driven piezoelectrocatalytic tumor immunoactivation opens a safe and efficient pathway for deep tumor therapy.

Photothermal-Triggered Sulfur Oxide Gas Therapy Augments Type I Photodynamic Therapy for Potentiating Cancer Stem Cell Ablation and Inhibiting Radioresistant Tumor Recurrence.

Despite advances in cancer therapy, the existence of self-renewing cancer stem cells (CSC) can lead to tumor recurrence and radiation resistance, resulting in treatment failure and high mortality in patients. To address this issue, a near-infrared (NIR) laser-induced synergistic therapeutic platform has been developed by incorporating aggregation-induced emission (AIE)-active phototheranostic agents and sulfur dioxide (SO2 ) prodrug into a biocompatible hydrogel, namely TBH, to suppress malignant CSC growth. Outstanding hydroxyl radical (·OH) generation and photothermal effect of the AIE phototheranostic agent actualizes Type I photodynamic therapy (PDT) and photothermal therapy through 660 nm NIR laser irradiation. Meanwhile, a large amount of SO2 is released from the SO2 prodrug in thermo-sensitive TBH gel, which depletes upregulated glutathione in CSC and consequentially promotes ·OH generation for PDT enhancement. Thus, the resulting TBH hydrogel can diminish CSC under 660 nm laser irradiation and finally restrain tumor recurrence after radiotherapy (RT). In comparison, the tumor in the mice that were only treated with RT relapsed rapidly. These findings reveal a double-boosting ·OH generation protocol, and the synergistic combination of AIE-mediated PDT and gas therapy provides a novel strategy for inhibiting CSC growth and cancer recurrence after RT, which presents great potential for clinical treatment.

Inhibition of free heme-catalyzed Fenton-like reaction prevents non-alcoholic fatty liver disease by hepatocyte-targeted hydrogen delivery.

The metabolic disorder of hepatocytes in non-alcoholic fatty liver disease (NAFLD) leads to the formation of an iron pool which induces the Fenton reaction-derived ferroptosis and the deterioration of liver disease. The elimination of the iron pool for the removal of Fenton reactions is vitally important to prevent the evolution of NAFLD, but quite challenging. In this work, we discover that free heme in the iron pool of NAFLD can catalyze the hydrogenation of H2O2/‧OH to block the heme-based Fenton reaction for the first time, and therefore develop a novel hepatocyte-targeted hydrogen delivery system (MSN-Glu) by modifying magnesium silicide nanosheets (MSN) with N-(3-triethoxysilylpropyl) gluconamide to block the heme-catalyzed vicious circle of liver disease. The developed MSN-Glu nanomedicine exhibits a high hydrogen delivery capacity as well as sustained hydrogen release and hepatocyte-targeting behaviors, and remarkably improves the metabolic function of the liver in a NAFLD mouse model by the relief of oxidative stress and the prevention of ferroptosis in hepatocytes, accelerating the removal of the iron pool in fundamental support of NAFLD prevention. The proposed prevention strategy based on the mechanisms of NAFLD disease and hydrogen medicine will provide an inspiration for inflammation-related disease prevention.

A strategy of local hydrogen capture and catalytic hydrogenation for enhanced therapy of chronic liver diseases.

Background: Chronic liver diseases (CLD) frequently derive from hepatic steatosis, inflammation and fibrosis, and become a leading inducement of cirrhosis and hepatocarcinoma. Molecular hydrogen (H2) is an emerging wide-spectrum anti-inflammatory molecule which is able to improve hepatic inflammation and metabolic dysfunction, and holds obvious advantages in biosafety over traditional anti-CLD drugs, but existing H2 administration routes cannot realize the liver-targeted high-dose delivery of H2, severely limiting its anti-CLD efficacy. Method: In this work, a concept of local hydrogen capture and catalytic hydroxyl radical (·OH) hydrogenation is proposed for CLD treatment. The mild and moderate non-alcoholic steatohepatitis (NASH) model mice were intravenously injected with PdH nanoparticles firstly, and then daily inhaled 4% hydrogen gas for 3 h throughout the whole treatment period. After the end of treatment, glutathione (GSH) was intramuscularly injected every day to assist the Pd excretion. Results: In vitro and in vivo proof-of-concept experiments have confirmed that Pd nanoparticles can accumulate in liver in a targeted manner post intravenous injection, and play a dual role of hydrogen captor and ·OH filter to locally capture/store the liver-passing H2 during daily hydrogen gas inhalation and rapidly catalyze the ·OH hydrogenation into H2O. The proposed therapy significantly improves the outcomes of hydrogen therapy in the prevention and treatment of NASH by exhibiting a wide range of bioactivity including the regulation of lipid metabolism and anti-inflammation. Pd can be mostly eliminated after the end of treatment under the assistance of GSH. Conclusion: Our study verified a catalytic strategy of combining PdH nanoparticles and hydrogen inhalation, which exhibited enhanced anti-inflammatory effect for CLD treatment. The proposed catalytic strategy will open a new window to realize safe and efficient CLD treatment.

Sonocatalytic hydrogen/hole-combined therapy for anti-biofilm and infected diabetic wound healing.

It is a great challenge to effectively eradicate biofilm and cure biofilm-infected diseases because dense extracellular polymeric substance matrix prevents routine antibacterial agents from penetrating into biofilm. H2 is an emerging energy-regulating molecule possessing both high biosafety and high tissue permeability. In this work, we propose a concept of sonocatalytic hydrogen/hole-combined 'inside/outside-cooperation' anti-biofilm for promoting bacteria-infected diabetic wound healing based on two-dimensional piezoelectric nanomaterials. Proof-of-concept experiments using C3N4 nanosheets as a representative piezoelectric catalyst with wide band gap and high biosafety have verified that sonocatalytically generated H2 and holes rapidly penetrate into biofilm to inhibit bacterial energy metabolism and oxidatively deprive polysaccharides/NADH in biofilm to destroy the bacterial membrane/electron transport chain, respectively, inside/outside-cooperatively eradicating biofilm. A bacteria-infected diabetic wound model is used to confirm the excellent in vivo antibacterial performance of sonocatalytic hydrogen/hole-combined therapy, remarkably improving bacteria-infected diabetic wound healing. The proposed strategy of sonocatalytic hole/hydrogen-combined 'inside/outside-cooperation' will make a highway for treatment of deep-seated biofilm infection.

Mesocrystalline ZnS nanoparticles-augmented sonocatalytic full water splitting into H2/O2 for immunoactivating deep tumor.

Therapeutic gas molecules have high tissue penetrability, but their sustainable supply and controlled release in deep tumor is a huge challenge. In this work, a concept of sonocatalytic full water splitting for hydrogen/oxygen immunotherapy of deep tumor is proposed, and a new kind of ZnS nanoparticles with a mesocrystalline structure (mZnS) is developed to achieve highly efficient sonocatalytic full water splitting for sustainable supply of H2 and O2 in tumor, achieving a high efficacy of deep tumor therapy. Mechanistically, locally generated hydrogen and oxygen molecules exhibit a tumoricidal effect as well as the co-immunoactivation of deep tumors through inducing the M2-to-M1 repolarization of intratumoral macrophages and the tumor hypoxia relief-mediated activation of CD8+ T cells, respectively. The proposed sonocatalytic immunoactivation strategy will open a new window to realize safe and efficient treatment of deep tumors.

Two-Dimensional Mg2 Si Nanosheet-Enabled Sustained Hydrogen Generation for Improved Repair and Regeneration of Deeply Burned Skin.

Molecular hydrogen holds a high potential for wound healing owing to its anti-inflammatory effect and high biosafety, but commonly used hydrogen administration routes hardly achieve the sustained supply of high-dosage hydrogen, limiting hydrogen therapy efficacy. Here, two-dimensional Mg2 Si nanosheet (MSN) is exploited as a super-persistent hydrogen-releasing nanomaterial with high biocompatibility, and the incorporation of MSN into the chitosan/hyaluronic acid hydrogel (MSN@CS/HA) is developed as a dressing to repair deeply burned skin. The MSN@CS/HA hydrogel dressing can continuously generate hydrogen molecules for about 1 week in the physiological conditions in support of local, long-term, and plentiful hydrogen supply and remarkably promotes the healing and regeneration of deep second-degree and third-degree burn wounds without visible scar and toxic side effect. Mechanistically, a sustained supply of hydrogen molecules induces anti-inflammatory M2 macrophage polarization in time by enhancing CCL2 (chemokine C-C motif ligand 2) expression to promote angiogenesis and reduce fibrosis and also enhances the proliferation and migration capability of skin cells directly and indirectly by locally scavenging overexpressed reactive oxygen species, synergistically favoring wound repair. The proposed synthesis method, therapeutic strategy, and mechanisms will open a window for synthesizing a variety of MSene nanomaterials and developing their various proangiogenesis applications besides wound healing.

NIR-photocatalytic regulation of arthritic synovial microenvironment.

Synovial microenvironment (SME) plays a vital role in the formation of synovial pannus and the induction of cartilage destruction in arthritis. In this work, a concept of the photocatalytic regulation of SME is proposed for arthritis treatment, and monodispersive hydrogen-doped titanium dioxide nanorods with a rutile single-crystal structure are developed by a full-solution method to achieve near infrared-photocatalytic generation of hydrogen molecules and simultaneous depletion of overexpressed lactic acid (LA) for realizing SME regulation in a collagen-induced mouse model of rheumatoid arthritis. Mechanistically, locally generated hydrogen molecules scavenge overexpressed reactive oxygen species to mediate the anti-inflammatory polarization of macrophages, while the simultaneous photocatalytic depletion of overexpressed LA inhibits the inflammatory/invasive phenotypes of synoviocytes and macrophages and ameliorates the abnormal proliferation of synoviocytes, thereby remarkably preventing the synovial pannus formation and cartilage destruction. The proposed catalysis-mediated SME regulation strategy will open a window to realize facile and efficient arthritis treatment.

Photocatalytic glucose depletion and hydrogen generation for diabetic wound healing.

High-glucose microenvironment in the diabetic foot ulcer (DFU) causes excessive glycation and induces chronic inflammation, leading to the difficulty of DFU healing. Hydrogen-rich water bath can promote the healing of DFU in clinic by virtue of the anti-inflammatory effect of hydrogen molecules, but the long-term daily soaking counts against the formation of a scab and cannot change the high-glucose microenvironment, limiting the outcome of DFU therapy. In this work, photocatalytic therapy of diabetic wound is proposed for sustainable hydrogen generation and local glucose depletion by utilizing glucose in the high-glucose microenvironment as a sacrificial agent. Hydrogen-incorporated titanium oxide nanorods are developed to realize efficient visible light (VIS)-responsive photocatalysis for glucose depletion and hydrogen generation, achieving a high efficacy of diabetic wound healing. Mechanistically, local glucose depletion and hydrogen generation jointly attenuate the apoptosis of skin cells and promote their proliferation and migration by inhibiting the synthesis of advanced glycation end products and the expression of their receptors, respectively. The proposed VIS-photocatalytic strategy provides a solution for facile, safe and efficient treatment of DFU.

A nanoconcrete welding strategy for constructing high-performance wound dressing.

Engineering biomaterials to meet specific biomedical applications raises high requirements of mechanical performances, and simultaneous strengthening and toughening of polymer are frequently necessary but very challenging in many cases. In this work, we propose a new concept of nanoconcrete welding polymer chains, where mesoporous CaCO3 (mCaCO3) nanoconcretes which are composed of amorphous and nanocrystalline phases are developed to powerfully weld polymer chains through siphoning-induced occlusion, hydration-driven crystallization and dehydration-driven compression of nanoconcretes. The mCaCO3 nanoconcrete welding technology is verified to be able to remarkably augment strength, toughness and anti-fatigue performances of a model polymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate)-based porous membrane. Mechanistically, we have revealed polymer-occluded nanocrystal structure and welding-derived microstress which is much stronger than interfacial Van der Waals force, thus efficiently preventing the generation of microcracks and repairing initial microcracks by microcracks-induced hydration, crystallization and polymer welding of mCaCO3 nanoconcretes. Constructed porous membrane is used as wound dressing, exhibiting a special nanoplates-constructed surface topography as well as a porous structure with plentiful oriented, aligned and opened pore channels, improved hydrophilicity, water vapor permeability, anti-bacterial and cell adherence, in support of wound healing and skin structural/functional repairing. The proposed nanoconcrete-welding-polymer strategy breaks a new pathway for improving the mechanical performances of polymers.

Light-triggered nitric oxide release and structure transformation of peptide for enhanced intratumoral retention and sensitized photodynamic therapy.

Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects. Unfortunately, nowadays the targeting efficiency of nanomedicine toward tumor is still quite limited and far from clinical requirements. In this work, we develop an innovative peptide-based nanoparticle to realize light-triggered nitric oxide (NO) release and structural transformation for enhanced intratumoral retention and simultaneously sensitizing photodynamic therapy (PDT). The designed nanoparticle is self-assembled from a chimeric peptide monomer, TPP-RRRKLVFFK-Ce6, which contains a photosensitive moiety (chlorin e6, Ce6), a ß-sheet-forming peptide domain (Lys-Leu-Val-Phe-Phe, KLVFF), an oligoarginine domain (RRR) as NO donor and a triphenylphosphonium (TPP) moiety for targeting mitochondria. When irradiated by light, the constructed nanoparticles undergo rapid structural transformation from nanosphere to nanorod, enabling to achieve a significantly higher intratumoral accumulation by 3.26 times compared to that without light irradiation. More importantly, the conversion of generated NO and reactive oxygen species (ROS) in a light-responsive way to peroxynitrite anions (ONOO-) with higher cytotoxicity enables NO to sensitize PDT in cancer treatment. Both in vitro and in vivo studies demonstrate that NO sensitized PDT based on the well-designed transformable nanoparticles enables to eradicate tumors efficiently. The light-triggered transformable nanoplatform developed in this work provides a new strategy for enhanced intratumoral retention and improved therapeutic outcome.

Acid-Degradable Hydrogen-Generating Metal-Organic Framework for Overcoming Cancer Resistance/Metastasis and Off-Target Side Effects.

The development of stimuli-responsively degradable porous carriers for both controlled drug release and high biosafety is vitally important to their clinical translation, but still challenging at present. A new type of porphyrin-iron metal organic framework (Fe-MOF) nanocrystals is engineered here as acid-degradable drug carrier and hydrogen donor by the coordination between porphyrin and zero-valence Fe atom. Fe-MOF nanocrystals exhibit excellent acid-responsive degradation for H2 generation and simultaneous release of the loaded drug for combined hydrogen-chemotherapy of cancer multidrug resistance (MDR) and metastasis and for local hydrogen eradication of the off-target induced toxic side effects of the drug to normal cells/tissues. Mechanistically, released H2 assists chemotherapeutic drug to efficiently inhibit cancer metastasis by immunoactivating intratumoral M1-phenotype macrophages and consequently downregulating the expression of metastasis-related matrix metalloproteinase-2 (MMP-2) and can also downregulate the expressions of both P-glycoprotein (P-gp) protein and adenosine triphosphate (ATP) in MDR cancer cells to sensitize chemotherapeutic drug for enhanced damage to mitochondria and DNA. High anti-MDR/antimetastasis efficacies and high biocompatibility endow Fe-MOF nanocrystals and the Fe-MOF-based nanomedicine with high potential for clinical translation.

An Activity-Based Ratiometric Fluorescent Probe for In†Vivo Real-Time Imaging of Hydrogen Molecules.

To reveal the biomedical effects and mechanisms of hydrogen molecules urgently needs hydrogen molecular imaging probes as an imperative tool, but the development of these probes is extremely challenging. A catalytic hydrogenation strategy is proposed to design and synthesize a ratiometric fluorescent probe by encapsulating Pd nanoparticles and conjugating azido-/coumarin-modified fluorophore into mesoporous silica nanoparticles, realizing in vitro and in vivo fluorescence imaging of hydrogen molecules. The developed hydrogen probe exhibits high sensitivity, rapid responsivity, high selectivity and low detection limit, enabling rapid and real-time detection of hydrogen molecules both in cells and in the body of animal and plant. By application of the developed fluorescent probe, we have directly observed the super-high transmembrane and ultrafast transport abilities of hydrogen molecules in cells, animals and plants, and discovered in vivo high diffusion of hydrogen molecules.

Engineering biocompatible TeSex nano-alloys as a versatile theranostic nanoplatform.

Photothermal nanotheranostics, especially in the near infrared II (NIR-II) region, exhibits a great potential in precision and personalized medicine, owing to high tissue penetration of NIR-II light. The NIR-II-photothermal nanoplatforms with high biocompatibility as well as high photothermal effect are urgently needed but rarely reported so far. Te nanomaterials possess high absorbance to NIR-II light but also exhibit high cytotoxicity, impeding their biomedical applications. In this work, the controllable incorporation of biocompatible Se into the lattice of Te nanostructures is proposed to intrinsically tune their inherent cytotoxicity and enhance their biocompatibility, developing TeSex nano-alloys as a new kind of theranostic nanoplatforms. We have uncovered that the cytotoxicity of Te nanomaterials primarily derives from irreversible oxidation stress and intracellular imbalance of organization and energy, and can be eliminated by incorporating a moderate proportion of Se (x=0.43). We have also discovered that the as-prepared TeSex nano-alloys have extraordinarily high NIR-II-photothermal conversion efficiency (77.2%), 64Cu coordination and computed tomography (CT) contrast capabilities, enabling high-efficacy multimodal photothermal/photoacoustic/positron emission tomography (PET)/CT imaging-guided NIR-II-photothermal therapy of cancer. The proposed nano-alloying strategy provides a new route to improve the biocompatibility of biomedical nanoplatforms and endow them with versatile theranostic functions.

Nanocapsule-mediated sustained H2 release in the gut ameliorates metabolic dysfunction-associated fatty liver disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is estimated to affect a quarter of all population and represents a major health threat to all societies. Yet, currently no approved pharmacological treatment is available for MAFLD. H2-rich water has recently been reported to reduce hepatic lipid accumulation in MAFLD patients but its efficacy is limited due to low H2 dosage. Increasing H2 dose may enhance its therapeutic effects but remains technically challenging. In this study, we designed and synthesized a hydrogen nanocapsule by encapsulating ammonia borane into hollow mesoporous silica nanoparticles to achieve ultrahigh and sustained H2 release in the gut. We then investigated its efficacy in treating early-stage MAFLD and other metabolic dysfunctions such as obesity and diabetes. The hydrogen nanocapsule attenuated both diet-induced and genetic mutation induced early-stage MAFLD, obesity, and diabetes in mice, without any tissue toxicity. Mechanistically, we discovered that sustained and ultrahigh H2 supply by hydrogen nanocapsule increased, among other species, the abundance of Akkermansia muciniphila, highlighting reshaped gut microbiota as a potential mechanism of H2 in treating metabolic dysfunctions. Moreover, hepatic transcriptome showed a reprogramed liver metabolism profile with reduced lipid synthesis and increased fatty acid metabolism.

MBene as a Theranostic Nanoplatform for Photocontrolled Intratumoral Retention and Drug Release.

Tumor-targeted drug delivery by nanomaterials is important to improve tumor therapy efficacy and reduce toxic side effects, but its efficiency is quite limited. In this work, a new type of MBene, zirconium boride nanosheet (ZBN), as a versatile nanoplatform to realize near-infrared (NIR)-controlled intratumoral retention and drug release is developed. ZBN exhibits high NIR-photothermal conversion efficiency (76.8%), surface modification with hyaluronic acid (HA) by polyol-borate esterfication endows ZBN-HA with good dispersion, and the photopyrolysis of borate ester causes HA detachment and ZBN aggregation, enabling NIR-controlled intratumoral retention to achieve high intratumoral accumulation. By virtue of surface borate esterfication, polyol chemotherapeutic drug (doxorubicin, DOX), and NO prodrug (ß-galactosyl-diazeniumdiolate, Gal-NO) can be efficiently and stably conjugated on the surface of ZBN-HA (1.21 g DOX or 0.57 g Gal-NO per gram ZBN) without visible drug leakage, and the photopyrolysis of borate ester enables NIR-controlled drug release with high responsiveness and controllability. Combined chemothermal/gasothermal therapies based on ZBN-HA/DOX and ZBN-HA/NO nanomedicines eradicate primary tumors and interdict tumor metastasis by changing the tumor microenvironment and killing cancer cells in primary tumors. The developed NIR-photothermal MBene is confirmed as a versatile nanoplatform capable of high-efficacy tumor-targeted drug delivery and controlled drug release.

Photocatalysis-mediated drug-free sustainable cancer therapy using nanocatalyst.

Drug therapy unavoidably brings toxic side effects and drug content-limited therapeutic efficacy although many nanocarriers have been developed to improve them to a certain extent. In this work, a concept of drug-free therapeutics is proposed and defined as a therapeutic methodology without the use of traditional toxic drugs, without the consumption of therapeutic agents during treatment but with the inexhaustible therapeutic capability to maximize the benefit of treatment, and a Z-scheme SnS1.68-WO2.41 nanocatalyst is developed to achieve near infrared (NIR)-photocatalytic generation of oxidative holes and hydrogen molecules for realizing combined hole/hydrogen therapy by the drug-free therapeutic strategy. Without the need of any drug and other therapeutic agent assistance, the nanocatalyst oxidizes/consumes intratumoral over-expressed glutathione (GSH) by holes and simultaneously generates hydrogen molecules in a lasting and controllable way under NIR irradiation. Mechanistically, generated hydrogen molecules and GSH consumption inhibit cancer cell energy and destroy intratumoral redox balance, respectively, to synergistically damage DNA and induce tumor cell apoptosis. High efficacy and biosafety of combined hole/hydrogen therapy of tumors are achieved by the nanocatalyst. The proposed catalysis-based drug-free therapeutic strategy breaks a pathway to realize high efficacy and low toxicity of cancer treatment.

A multistage assembly/disassembly strategy for tumor-targeted CO delivery.

CO gas molecule not only could selectively kill cancer cells but also exhibits limited anticancer efficacy because of the lack of active tumor-targeted accumulation capability. In this work, a multistage assembly/disassembly strategy is developed to construct a new intelligent nanomedicine by encapsulating a mitochondria-targeted and intramitochondrial microenvironment-responsive prodrug (FeCO-TPP) within mesoporous silica nanoparticle that is further coated with hyaluronic acid by step-by-step electrostatic assembly, realizing tumor tissue-cell-mitochondria-targeted multistage delivery and controlled release of CO in a step-by-step disassembly way. Multistage targeted delivery and controlled release of CO involve (i) the passive tumor tissue-targeted nanomedicine delivery, (ii) the active tumor cell-targeted nanomedicine delivery, (iii) the acid-responsive prodrug release, (iv) the mitochondria-targeted prodrug delivery, and (v) the ROS-responsive CO release. The developed nanomedicine has effectively augmented the efficacy and safety of CO therapy of cancer both in vitro and in vivo. The proposed multistage assembly/disassembly strategy opens a new window for targeted CO therapy.