An O2 Self‐Sufficient Biomimetic Nanoplatform for Highly Specific and Efficient Photodynamic Therapy

Conventional oxygen‐dependent photodynamic therapy (PDT) has faced severe challenges because of the non‐specificity of most available photosensitizers (PSs) and the hypoxic nature of tumor tissues. Here, an O₂ self‐sufficient cell‐like biomimetic nanoplatform (CAT‐PS‐ZIF@Mem) consisting of the cancer cell membrane (Mem) and a cytoskeleton‐like porous zeolitic imidazolate framework (ZIF‐8) with the embedded catalase (CAT) protein molecules and Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS₄, defined as PS) is developed. Because of the immunological response and homologous targeting abilities of the cancer cell membrane, CAT‐PS‐ZIF@Mem is selectively accumulated at the tumor site and taken up effectively by tumor cells after intravenous injection. After the intracellular H₂O₂ penetration into the framework, it is catalyzed by CAT to produce O₂ at the hypoxic tumor site, facilitating the generation of toxic ¹O₂ for highly effective PDT in vivo under near‐infrared irradiation. By integrating the immune escape, cell homologous recognition, and O₂ self‐sufficiency, this cell‐like biomimetic nanoplatform demonstrates highly specific and efficient PDT against hypoxic tumor cells with much reduced side‐effect on normal tissues.     

Co–Ferrocene MOF/Glucose Oxidase as Cascade Nanozyme for Effective Tumor Therapy

Chemodynamic therapy (CDT), enabling selective therapeutic effects and low side effect, attracts increasing attention in recent years. However, limited intracellular content of H₂O₂ and acid at the tumor site restrains the lasting Fenton reaction and thus the anticancer efficacy of CDT. Herein, a nanoscale Co–ferrocene metal–organic framework (Co‐Fc NMOF) with high Fenton activity is synthesized and combined with glucose oxidase (GOx) to construct a cascade enzymatic/Fenton catalytic platform (Co‐Fc@GOx) for enhanced tumor treatment. In this system, Co‐Fc NMOF not only acts as a versatile and effective delivery cargo of GOx molecules to modulate the reaction conditions, but also possesses excellent Fenton effect for the generation of highly toxic ?OH. In the tumor microenvironment, GOx delivered by Co‐Fc NMOF catalyzes endogenous glucose to gluconic acid and H₂O₂. The intracellular acidity and the on‐site content of H₂O₂ are consequently promoted, which in turn favors the Fenton reaction of Co‐Fc NMOF and enhances the generation of reactive oxygen species (ROS). Both in vitro and in vivo results demonstrate that this cascade enzymatic/Fenton catalytic reaction triggered by Co‐Fc@GOx nanozyme enables remarkable anticancer properties.     

Persistent Regulation of Tumor Microenvironment via Circulating Catalysis of MnFe2O4@Metal–Organic Frameworks for Enhanced Photodynamic Therapy

Reactive oxygen species (ROS)‐based cancer therapy, such as photodynamic therapy (PDT), is subject to the hypoxia and overexpressed glutathione (GSH) found in the tumor microenvironment (TME). Herein, a novel strategy is reported to continuously and simultaneously regulate tumor hypoxia and reducibility in order to achieve the desired therapeutic effect. To accomplish this, a biocompatible nanoplatform (MnFe₂O₄@metal–organic framework (MOF)) is developed by integrating a coating of porphyrin‐based MOF as the photosensitizer and manganese ferrite nanoparticle (MnFe₂O₄) as the nanoenzyme. The synthetic MnFe₂O₄@MOF nanoplatform exhibits both catalase‐like and glutathione peroxidase‐like activities. Once internalized in the tumor, the nanoplatform can continuously catalyze H₂O₂ to produce O₂ to overcome the tumor hypoxia by cyclic Fenton reaction. Meanwhile, combined with the Fenton reaction, MnFe₂O₄@MOF is able to persistently consume GSH in the presence of H₂O₂, which decreases the depletion of ROS upon laser irradiation during PDT and achieves better therapeutic efficacy in vitro and in vivo. Moreover, the nanoplatform integrates a treatment modality with magnetic resonance imaging, along with persistent regulation of TME, to promote more precise and effective treatment for future clinical application.     

An O2 Self‐Supplementing and Reactive‐Oxygen‐Species‐Circulating Amplified Nanoplatform via H2O/H2O2 Splitting for Tumor Imaging and Photodynamic Therapy

Conventional photodynamic therapy (PDT) has limited applications in clinical cancer therapy due to the insufficient O₂ supply, inefficient reactive oxygen species (ROS) generation, and low penetration depth of light. In this work, a multifunctional nanoplatform, upconversion nanoparticles (UCNPs)@TiO₂@MnO₂ core/shell/sheet nanocomposites (UTMs), is designed and constructed to overcome these drawbacks by generating O₂ in situ, amplifying the content of singlet oxygen (¹O₂) and hydroxyl radical (?OH) via water‐splitting, and utilizing 980 nm near‐infrared (NIR) light to increase penetration depth. Once UTMs are accumulated at tumor site, intracellular H₂O₂ is catalyzed by MnO₂ nanosheets to generate O₂ for improving oxygen‐dependent PDT. Simultaneously, with the decomposition of MnO₂ nanosheets and 980 nm NIR irradiation, UCNPs can efficiently convert NIR to ultraviolet light to activate TiO₂ and generate toxic ROS for deep tumor therapy. In addition, UCNPs and decomposed Mn²⁺ can be used for further upconversion luminescence and magnetic resonance imaging in tumor site. Both in vitro and in vivo experiments demonstrate that this nanoplatform can significantly improve PDT efficiency with tumor imaging capability, which will find great potential in the fight against tumor.     

Oxygen‐Generating MnO2 Nanodots‐Anchored Versatile Nanoplatform for Combined Chemo‐Photodynamic Therapy in Hypoxic Cancer

Local hypoxia in tumors results in undesirable impediments for the efficiencies of oxygen‐dependent chemical and photodynamic therapy (PDT). Herein, a versatile oxygen‐generating and pH‐responsive nanoplatform is developed by loading MnO₂ nanodots onto the nanosystem that encapsulates g‐C₃N₄ and doxorubicin hydrochloride to overcome the hypoxia‐caused resistance in cancer therapy. The loaded MnO₂ nanodots can react with endogenous acidic H₂O₂ to elevate the dissolved oxygen concentration, leading to considerably enhanced cancer therapy efficacy. As such, the as‐prepared nanoplatform with excellent dispersibility and satisfactory biocompatibility can sustainably increase the oxygen concentration and rapidly release the encapsulated drugs in acid H₂O₂ environment. In vitro cytotoxicity experiments show a higher therapy effect by the designed nanoplatform, when compared to therapy without MnO₂ nanodots under hypoxia condition, or chemical and photodynamic therapy alone with the presence of MnO₂ nanodots. In vivo experiments also demonstrate that 4T1 tumors can be very efficiently eliminated by the designed nanoplatform under light irradiation. These results highlight that the MnO₂ nanodots‐based nanoplatform is promising for elevating the oxygen level in tumor microenvironments to overcome hypoxia limitations for high‐performance cancer therapy.     

A Near-Infrared Light-Responsive ROS Cascade Nanoplatform for Synergistic Therapy Potentiating Antitumor Immune Responses

Tumor occurrence is closely related to the unlimited proliferation and the evasion of the immune surveillance. However, it remains a challenge to kill tumor cells and simultaneously activate antitumor immunity upon spatially localized external stimuli. Herein, a robust tumor synergistic therapeutic nanoplatform is designed in combination with dual photosensitizers-loaded upconversion nanoparticles (UCNPs) and ferric-tannic acid (FeTA) nanocomplex. Dual photosensitizers-loaded UCNPs can induce photodynamic therapy (PDT) effect by generation of cytotoxic reactive oxygen species (ROS) on demand under near-infrared (NIR) light irradiation. FeTA can robustly respond to acidic tumor microenvironment to produce Fe²⁺ and subsequently induce chemodynamic therapy (CDT) by reacting with H₂O₂ in the tumor microenvironment. More importantly, the CDT/PDT synergy can not only exhibit significant antitumor ability but also induce ROS cascade to evoke immunogenic cell death. It increases tumor immunogenicity and promotes immune cell infiltration at tumor sites allowing further introduction of systemic immunotherapy responsiveness to inhibit the primary and distant tumor growth. This study provides a potential tumor microenvironment-responsive nanoplatform for imaging-guided diagnosis and combined CDT/PDT with improved immunotherapy responses and an external NIR-light control of photoactivation.     

MnO2 Gatekeeper: An Intelligent and O2‐Evolving Shell for Preventing Premature Release of High Cargo Payload Core,Overcoming Tumor Hypoxia,and Acidic H2O2‐Sensitive MRI

Premature leakage of photosensitizer (PS) from nanocarriers significantly reduces the accumulation of PS within a tumor, thereby enhancing nonspecific accumulation in normal tissues, which inevitably leads to a limited efficacy for photodynamic therapy (PDT) and the enhanced systematic phototoxicity. Moreover, local hypoxia of the tumor tissue also seriously hinders the PDT. To overcome these limitations, an acidic H₂O₂‐responsive and O₂‐evolving core–shell PDT nanoplatform is developed by using MnO₂ shell as a switchable shield to prevent the premature release of loaded PS in core and elevate the O₂ concentration within tumor tissue. The inner core SiO₂‐methylene blue obtained by co‐condensation has a high PS payload and the outer MnO₂ shell shields PS from leaking into blood after intravenous injection until reaching tumor tissue. Moreover, the shell MnO₂ simultaneously endows the theranostic nanocomposite with redox activity toward H₂O₂ in the acidic microenvironment of tumor tissue to generate O₂ and thus overcomes the hypoxia of cancer cells. More importantly, the Mn(ΙΙ) ion reduced from Mn(ΙV) is capable of in vivo magnetic resonance imaging selectively in response to overexpressed acidic H₂O₂. The facile incorporation of the switchable MnO₂ shell into one multifunctional diagnostic and therapeutic nanoplatform has great potential for future clinical application.     

Self-Tandem Bio-Heterojunctions Empower Orthopedic Implants with Amplified Chemo-Photodynamic Anti-Pathogenic Therapy and Boosted Diabetic Osseointegration

Hyperglycemic microenvironment in diabetes mellitus inevitably stalls the normal orchestrated course of bone regeneration and encourages pathogenic multiplication. Photodynamic therapy (PDT) and chemo-dynamic therapy (CDT) are extensively harnessed to combat pathogens, yet deep-seated diabetic bone defect has difficulty in supplying sufficient oxygen (O₂) and hydrogen peroxide (H₂O₂) stocks, resulting in inferior therapeutic efficiency. To address the tough plaguing, the self-tandem bio-heterojunctions (bio-HJs) consisting of molybdenum disulfide (MoS₂), graphene oxide (GO), and glucose oxidase (GOx) are constructed on orthopedic polyetheretherketone (PEEK) implants (SP-Mo/G@GOx) for amplified chemo-photodynamic anti-pathogenic therapy and boosted osseointegration in the deep-seated diabetic micromilieu. In this system, GOx exhausts glucose to generate H₂O₂, which provides an abundant stock for CDT. Besides, the bio-HJs produce hyperthermia upon near-infrared light (NIR) to accelerate the dynamic process, which amplifies the antibacterial potency of PDT by promoting the vast yield of singlet oxygen (¹O₂) in a self-tandem manner. More importantly, in vivo and in vitro assays demonstrate that the engineered implants exert a captivated bactericidal ability and significantly boost osseointegration in an infectious diabetic bone defect model. As envisaged, this study furnishes a novel tactic to arm orthopedic implants with self-tandem capability for the remedy of infectious diabetic bone defects.     

Stepwise Degradable Nanocarriers Enabled Cascade Delivery for Synergistic Cancer Therapy

Hypoxia‐activated prodrugs have brought new opportunities for safe and effective tumor ablation, but their therapeutic efficacy is limited by insufficient activation in tumor microenvironments. Herein, a novel cascade delivery system with tandem functions by integrating a hypoxia‐activated prodrug (AQ4N) and glucose oxidase (GOx) is designed to improve its efficacy. Innovative yolk–shell organosilica nanoparticles with a tetrasulfide bridged composition, a small‐pore yolk, and a large‐pore shell featuring a shell‐to‐yolk stepwise degradability are constructed as a carrier for AQ4N and GOx, one enzyme that catalyzes the oxidation of glucose to produce hydrogen peroxide. The glutathione (GSH) is depleted by tetrasulfide bond in the framework and induces shell degradation for fast release of GOx, which in turn induces starvation (glucose removal), oxidative cytotoxicity (H₂O₂ production and GSH depletion), and hypoxia (oxygen consumption). Finally, the hypoxia activates the liberated prodrug AQ4N for chemotherapy. The cascading and synergistic functions including GSH depletion, starvation, oxidative cytotoxicity, and chemotherapy lead to improved performance in tumor inhibition and antimetastasis.     

Light‐Triggered Clustered Vesicles with Self‐Supplied Oxygen and Tissue Penetrability for Photodynamic Therapy against Hypoxic Tumor

Smart nanocarriers are of particular interest for highly effective photodynamic therapy (PDT) in the field of precision nanomedicine. Nevertheless, a critical challenge still remains in the exploration of potent PDT treatment against hypoxic tumor. Herein, light‐triggered clustered polymeric vesicles for photoinduced hypoxic tumor ablation are demonstrated, which are able to deeply penetrate into the tumor and simultaneously afford oxygen supply upon light irradiation. Hydrogen peroxide (H₂O₂) and poly(amidoamine) dendrimer conjugating chlorin e6/cypate (CC‐PAMAM) are coassembled with reactive‐oxygen‐species‐responsive triblock copolymer into the polymeric vesicles. Upon 805 nm irradiation, the vesicles exhibit the light‐triggered thermal effect that is able to decompose H₂O₂ into O₂, which distinctly ensures the alleviation of tumor hypoxia at tumor. Followed by 660 nm irradiation, the vesicles are rapidly destabilized through singlet oxygen‐mediated cleavage of copolymer under light irradiation and thus allow the release of photoactive CC‐PAMAM from the vesicular chambers, followed by their deep penetration in the poorly permeable tumor. Consequently, the light‐triggered vesicles with both self‐supplied oxygen and deep tissue penetrability achieve the total ablation of hypoxic hypopermeable pancreatic tumor through photodynamic damage. These findings represent a general and smart nanoplatform for effective photoinduced treatment against hypoxic tumor.     

Low‐Dose X‐ray Activation of W(VI)‐Doped Persistent Luminescence Nanoparticles for Deep‐Tissue Photodynamic Therapy

Although photodynamic therapy (PDT) has served as an important strategy for treatment of various diseases, it still experiences many challenges, such as shallow penetration of light, high‐dose light irradiation, and low therapy efficiency in deep tissue. Here, a low‐dose X‐ray‐activated persistent luminescence nanoparticle (PLNP)‐mediated PDT nanoplatform for depth‐independent and repeatable cancer treatment has been reported. In order to improve therapeutic efficiency, this study first synthesizes W(VI)‐doped ZnGa₂O₄:Cr PLNPs with stronger persistent luminescence intensity and longer persistent luminescence time than traditional ZnGa₂O₄:Cr PLNPs. The proposed PLNPs can serve as a persistent excitation light source for PDT, even after X‐ray irradiation has been removed. Both in vitro and in vivo experiments demonstrate that low‐dose (0.18 Gy) X‐ray irradiation is sufficient to activate the PDT nanoplatform and causes significant inhibitory effect on tumor progression. Therefore, such PDT nanoplatform will provide a promising depth‐independent treatment mode for clinical cancer therapy in the future.     

A Robust ROS Generation Strategy for Enhanced Chemodynamic/Photodynamic Therapy via H2O2/O2 Self-Supply and Ca2+ Overloading

The efficacy of cancer therapy with reactive oxygen species (ROS) as the main therapeutic medium suffers from a deficiency of oxy-substrates, for example, insufficient endogenous hydrogen peroxide (H₂O₂) in chemodynamic therapy (CDT) and inherent hypoxia in photodynamic therapy (PDT). Herein, a smart polyethylene glycol (PEG)-ylated nanosystem CaO₂@ZIF-Fe/Ce6@PEG (abbreviation as CaZFCP) is constructed to achieve H₂O₂/O₂ self-supply and Ca²⁺ overloading in tumor cells simultaneously for enhanced CDT/PDT. Under the weakly acidic tumor microenvironment, the activity components inside CaZFCP, that is, CaO₂ nanoparticles, Fe²⁺, and photosensitizer Chlorin e6 (Ce6) are released by the degradation of zeolitic imidazole framework-90 (ZIF-90). Thereinto, CaO₂ nanoparticles are further decomposed to generate H₂O₂ and O₂, which alleviates both the insufficient endogenous H₂O₂ and hypoxia in tumor area, thus enhancing the efficiency of CDT and PDT by producing more hydroxyl radicals and singlet oxygen. Furthermore, Ca²⁺ overloading induced by the decomposition of CaO₂ is available for amplifying intracellular oxidative stress, resulting in mitochondrial dysfunction, which further improves the efficacy of combined CDT/PDT. In vitro and in vivo experimental results confirm excellent tumor inhibition effect, which also provides a facile paradigm in ROS-involved cancer therapies.     

A Novel Theranostic Nanoplatform Based on Pd@Pt‐PEG‐Ce6 for Enhanced Photodynamic Therapy by Modulating Tumor Hypoxia Microenvironment

Photodynamic therapy (PDT), which utilizes reactive oxygen species to kill cancer cells, has found wide applications in cancer treatment. However, the hypoxic nature of most solid tumors can severely restrict the efficiency of PDT. Meanwhile, the hydrophobicity and limited tumor selectivity of some photosensitizers also reduce their PDT efficacy. Herein, a photosensitizer‐Pd@Pt nanosystem (Pd@Pt‐PEG‐Ce6) is designed for highly efficient PDT by overcoming these limitations. In the nanofabrication, Pd@Pt nanoplates, exhibiting catalase‐like activity to decompose H₂O₂ to generate oxygen, are first modified with bifunctional PEG (SH‐PEG‐NH₂). Then the Pd@Pt‐PEG is further covalently conjugated with the photosensitizer chlorin e6 (Ce6) to get Pd@Pt‐PEG‐Ce6 nanocomposite. The Pd@Pt‐PEG‐Ce6 exhibits good biocompatibility, long blood circulation half‐life, efficient tumor accumulation, and outstanding imaging properties. Both in vitro and in vivo experimental results clearly indicate that Pd@Pt‐PEG‐Ce6 effectively delivers photosensitizers to cancer cells/tumor sites and triggers the decomposition of endogenous H₂O₂ to produce oxygen, resulting in a remarkably enhanced PDT efficacy. Moreover, the moderate photothermal effect of Pd@Pt nanoplates also strengthen the PDT of Pd@Pt‐PEG‐Ce6. Therefore, by integrating the merits of high tumor‐specific accumulation, hypoxia modulation function, and mild photothermal effect into a single nanoagent, Pd@Pt‐PEG‐Ce6 readily acts as an ideal nanotherapeutic platform for enhanced cancer PDT.     

Tumor Microenvironment‐Responsive Mesoporous MnO2‐Coated Upconversion Nanoplatform for Self‐Enhanced Tumor Theranostics

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO₂) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO₂) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO₂ shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO₂ degrades rapidly within the TME, releasing Mn²⁺ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO₂ shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H₂O₂ and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.     

Modulation of Hypoxia in Solid Tumor Microenvironment with MnO2 Nanoparticles to Enhance Photodynamic Therapy

Hypoxia not only promotes tumor metastasis but also strengthens tumor resistance to therapies that demand the involvement of oxygen, such as radiation therapy and photodynamic therapy (PDT). Herein, taking advantage of the high reactivity of manganese dioxide (MnO₂) nanoparticles toward endogenous hydrogen peroxide (H₂O₂) within the tumor microenvironment to generate O₂, multifunctional chlorine e6 (Ce6) loaded MnO₂ nanoparticles with surface polyethylene glycol (PEG) modification (Ce6@MnO₂‐PEG) are formulated to achieve enhanced tumor‐specific PDT. In vitro studies under an oxygen‐deficient atmosphere uncover that Ce6@MnO₂‐PEG nanoparticles could effectively enhance the efficacy of light‐induced PDT due to the increased intracellular O₂ level benefited from the reaction between MnO₂ and H₂O₂, the latter of which is produced by cancer cells under the hypoxic condition. Owing to the efficient tumor homing of Ce6@MnO₂‐PEG nanoparticles upon intravenous injection as revealed by T1‐weighted magnetic resonance imaging, the intratumoral hypoxia is alleviated to a great extent. Thus, in vivo PDT with Ce6@MnO₂‐PEG nanoparticles even at a largely reduced dose offers remarkably improved therapeutic efficacy in inhibiting tumor growth compared to free Ce6. The results highlight the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome current limitations of cancer therapies.     

Reactive Oxygen Species–Activatable Liposomes Regulating Hypoxic Tumor Microenvironment for Synergistic Photo/Chemodynamic Therapies

Tumors have adapted various cellular antidotes and microenvironmental conditions to subsist against photodynamic therapy (PDT) and chemodynamic therapy (CDT). Here, the development of reactive oxygen species (ROS)‐activatable liposomes (RALP) for therapeutic enhancement by simultaneously addressing the critical questions in PDT and CDT is reported. The design of RALP@HOC@Fe₃O₄ features ROS‐cleavable linker molecules for improved tumor penetration/uptake and ondemand cargo releasing, and integration of Fe₃O₄ and an oxaliplatin prodrug for smart regulation of hypoxia tumor microenvironment. Glutathione stored by the tumor cells is consumed by the prodrug to produce highly toxic oxaliplatin. Depletion of glutathione not only avoids the undesired annihilation of ROS in PDT, but also modulates the chemical specie equilibria in tumors for H₂O₂ promotion, leading to greatly relieved tumor hypoxia and PDT enhancement. Synergistically, Fe (II) in the hybrid RALP formulation can be fuelled by H₂O₂ to generate ?OH in the Fenton reaction, thus elevating CDT efficiency. This work offers a strategy for harnessing smart, responsive, and biocompatible liposomes to enhance PDT and CDT by regulating tumor microenvironment, highlighting a potential clinical translation beneficial to patients with cancer.     

Fluorinated Polyethylenimine to Enable Transmucosal Delivery of Photosensitizer‐Conjugated Catalase for Photodynamic Therapy of Orthotopic Bladder Tumors Postintravesical Instillation

Photodynamic therapy (PDT) by insertion of an optical fiber into the bladder cavity has been applied in the clinic for noninvasive treatment of bladder tumors. To avoid systemic phototoxicity, bladder intravesical instillation of a photosensitizer may be an ideal approach for PDT treatment of bladder cancer, in comparison to conventional intravenous injection. However, the instillation‐based PDT for bladder cancer treatment remains to be less effective due to the poor urothelial uptake of photosensitizer, as well as the tumor hypoxia‐associated PDT resistance. Herein, it is uncovered that fluorinated polyethylenimine (F‐PEI) achieved by mixing with Chorin‐e6‐conjugated catalase (CAT‐Ce6) is able to form self‐assembled CAT‐Ce6/F‐PEI nanoparticles, which show greatly improved cross‐membrane, transmucosal, and intratumoral penetration capacities compared with CAT‐Ce6 alone or nonfluorinated CAT‐Ce6/PEI nanoparticles. Owing to the decomposition of tumor endogenous H₂O₂ by CAT‐Ce6/F‐PEI nanoparticles penetrating into bladder tumors, the tumor hypoxia would be effectively relieved to further favor PDT. Therefore, bladder intravesical instillation with CAT‐Ce6/F‐PEI nanoparticles could offer remarkably improved photodynamic therapeutic effect to destruct orthotopic bladder tumors with reduced systemic toxicity compared to hematoporphyrin, the first‐line photosensitizer used for bladder cancer PDT in clinic. This work presents a unique photosensitizer nanomedicine formulation, promising for clinical translation in instillation‐based PDT to treat bladder tumors.     

A Copper Single-Atom Cascade Bionanocatalyst for Treating Multidrug-Resistant Bacterial Diabetic Ulcer

Diabetic ulcers induced by multidrug-resistant (MDR) bacteria have severely endangered diabetic populations. These ulcers are very challenging to treat because the local high glucose concentration can both promote bacterial growth and limit the immune system's bactericidal action. Herein, a glucose oxidase-peroxidase (GOx-POD) dual-enzyme mimetic (DEM) bionanocatalyst, Au@CuBCats is synthesized to simultaneously control glucose concentration and bacteria in diabetic ulcers. Specifically, the AuNPs can serve as GOx mimics and catalyze the oxidation of glucose for the formation of H₂O₂; the H₂O₂ can then be further catalytically converted into OH via the POD-mimetic copper single atoms. Notably, the unique copper single atoms coordinated by one oxygen and two nitrogen atoms (CuN₂O₁) exhibit better POD catalytic performance than natural peroxidase. Further DFT calculations are conducted to study the catalytic mechanism and reveal the advantage of this CuN₂O₁ structure as compared to other copper single-atom sites. Both in vitro and in vivo experiments confirm the outstanding antibacterial therapeutic efficacy of the DEM bionanocatalyst. This new bionanocatalyst will provide essential insights for the next generation of antibiotic-free strategies for combating MDR bacterial diabetic ulcers, and also offer inspiration for designing bionanocatalytic cascading medicines.     

Porphyrin MOF Dots–Based,Function‐Adaptive Nanoplatform for Enhanced Penetration and Photodynamic Eradication of Bacterial Biofilms

Recently, antimicrobial photodynamic therapy (aPDT) has been considered as an attractive treatment option for biofilms ablation. However, even very efficient photosensitizers (PSs) still need high light doses and PS concentrations to eliminate biofilms due to the limited penetration and diffusion of PSs in biofilms. Moreover, the hypoxic microenvironment and rapid depletion of oxygen during PDT severely limit their therapeutic effects. Herein, for the first time, a porphyrin‐based metal organic framework (pMOF) dots–based nanoplatform with effective biofilm penetration, self‐oxygen generation, and enhanced photodynamic efficiency is synthesized for bacterial biofilms eradication. The function‐adaptive nanoplatform is composed of pMOF dots encapsulated by human serum albumin–coated manganese dioxide (MnO₂). The pH/H₂O₂‐responsive decomposition of MnO₂ in biofilms triggers the release of ultra‐small and positively charged pMOF dots and simultaneously generates O₂ in situ to alleviate hypoxia for biofilms. The released pMOF dots with high reactive oxygen species yield can effectively penetrate into biofilms, strongly bind with bacterial cell surface, and ablate bacterial biofilms. Importantly, such a nanoplatform can realize great therapeutic outcomes for treatment of Staphylococcus aureus–infected subcutaneous abscesses in vivo without damage to healthy tissues, which offers a promising strategy for efficient biofilms eradication.     

A Versatile Pt‐Based Core–Shell Nanoplatform as a Nanofactory for Enhanced Tumor Therapy

Hypoxia, one of the representative characteristics in solid tumors, not only reduces the effectiveness of multiple treatments, but also relates to the tumor invasion and metastasis. Here, a hybrid core–shell nanoplatform to produce adequate oxygen, supporting for more effective tumor treatment, is developed. Composed of polydopamine cores, platinum nanoparticle interlayers, and zirconium‐porphyrin (PCN) shells, the hybrid core–shell nanoplatform works like a nanofactory, providing necessary products at different time and space. Platinum nanoparticle interlayers can catalyze the endogenous H₂O₂ to O₂, which plays a dual rule in the enhanced tumor treatment. In the presence of light irradiation, O₂ can be converted into the lethal reactive oxygen species by the PCN shell. In the absence of light irradiation, O₂ ameliorates the hypoxic microenvironment, thereby reduces the invasion and metastasis of the tumor. Through a synergism of enhanced treatment and reduced metastasis, tumors could be treated more vigorously.