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.     

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.     

Precise Molecular Engineering of Photosensitizers with Aggregation‐Induced Emission over 800 nm for Photodynamic Therapy

Owing to efficient singlet oxygen (¹O₂) generation in aggregate state, photosensitizers (PSs) with aggregation‐induced emission (AIE) have attracted much research interests in photodynamic therapy (PDT). In addition to high ¹O₂ generation efficiency, strong molar absorption in long‐wavelength range and near‐infrared (NIR) emission are also highly desirable, but difficult to achieve for AIE PSs since the twisted structures in AIE moieties usually lead to absorption and emission in short‐wavelength range. In this contribution, through acceptor engineering, a new AIE PS of TBT is designed to show aggregation‐induced NIR emission centered at 810 nm, broad absorption in the range between 300 and 700 nm with a large molar absorption coefficient and a high ¹O₂ generation efficiency under white light irradiation. Further, donor engineering by attaching two branched flexible chains to TBT yielded TBTC8 , which circumvented the strong intermolecular interactions of TBT in nanoparticles (NPs), yielding TBTC8 NPs with optimized overall performance in ¹O₂ generation, absorption, and emission. Subsequent PDT results in both in vitro and in vivo studies indicate that TBTC8 NPs are promising candidates in practical application.     

Biodegradable Calcium Phosphate Nanotheranostics with Tumor-Specific Activatable Cascade Catalytic Reactions-Augmented Photodynamic Therapy

Photodynamic therapy (PDT) is exploited as a promising strategy for cancer treatment. However, the hypoxic solid tumor and the lack of tumor-specific photosensitizer administration hinder the further application of oxygen (O₂)-dependent PDT. In this study, a biodegradable and O₂ self-supplying nanoplatform for tumor microenvironment (TME)-specific activatable cascade catalytic reactions-augmented PDT is reported. The nanoplatform (named GMCD) is constructed by coloading catalase (CAT) and sinoporphyrin sodium (DVDMS) in the manganese (Mn)-doped calcium phosphate mineralized glucose oxidase (GOx) nanoparticles. The GMCD can effectively accumulate in tumor sites to achieve an “off to on” fluorescence transduction and a TME-activatable magnetic resonance imaging. After internalization into cancer cells, the endogenous hydrogen peroxide (H₂O₂) can be catalyzed to generate O₂ by CAT, which not only promotes GOx catalytic reaction to consume more intratumoral glucose, but also alleviates tumor hypoxia and enhances the production of cytotoxic singlet oxygen from light-triggered DVDMS. Moreover, the H₂O₂ generated by GOx-catalysis can be converted into highly toxic hydroxyl radicals by Mn²⁺-mediated Fenton-like reaction, further amplifying the oxidative damage of cancer cells. As a result, GMCD displays superior therapeutic effects on 4T1-tumor bearing mice by a long term cascade catalytic reactions augmented PDT.     

Glutathione‐Activatable and O2/Mn2+‐Evolving Nanocomposite for Highly Efficient and Selective Photodynamic and Gene‐Silencing Dual Therapy

Photodynamic therapy (PDT) has been applied in cancer treatment by converting O₂ into reactive singlet oxygen (¹O₂) to kill cancer cells. However, the effectiveness of PDT is limited by the fact that tumor hypoxia causes an inadequate O₂ supply, and the overexpressed glutathione (GSH) in cancer cells consumes reactive oxygen species. Herein, a multifunctional hybrid system is developed for selective and highly efficient PDT as well as gene‐silencing therapy using a novel GSH‐activatable and O₂/Mn²⁺‐evolving nanocomposite (GAOME NC). This system consists of honeycomb MnO₂ (hMnO₂) nanocarrier loaded with catalase, Ce6, and DNAzyme with folate label, which can specifically deliver payloads into cancer cells. Once endocytosed, hMnO₂ carriers are reduced by the overexpressed GSH to Mn²⁺ ions, resulting in the reduction of GSH level and disintegration of GAOME NC. The released catalases then trigger the breakdown of endogenous H₂O₂ to generate O₂, which is converted by the excited Ce6 into ¹O₂. The self‐sufficiency of O₂ and consumption of GSH effectively enhance the PDT efficacy. Moreover, DNAzyme is freed for gene silencing in the presence of self‐generated Mn²⁺ ions as cofactors. The rational synergy of enhanced PDT and gene‐silencing therapy remarkably improve the in vitro and in vivo therapeutic efficacy of cancers.     

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.     

Heptamethine Cyanine-Based Nanotheranostics with Catalase-Like Activity for Synergistic Phototherapy of Cancer

Single-molecule photosensitizers (PSs) for synergistic phototherapy are desirable but highly challenging, due to the competitive relationship between photothermal (PTT) and photodynamic therapy (PDT). Herein, a supramolecular strategy is developed that can tune the stacking pattern of PS molecules in their aggregates to optimize the PTT/PDT efficiency. Specifically, near-infrared (NIR) heptamethine cyanines (Cy7) are synthesized using tricyanofuran (TCF) as the acceptor and benzothiazole (BTH)/indole (IND) as the donor, where BTH is a less hydrogen-bonded tecton relative to IND. Both IND-Cy7-TCF and BTH-Cy7-TCF have similar photophysical properties at the molecular level, but BTH-Cy7-TCF in aggregated state exhibits higher singlet oxygen quantum yield (1.3% vs 0.2%) and competitive photothermal conversion efficiency (56.4% vs 62.3%) compared to IND-Cy7-TCF, due to the fine-tuning of hydrogen bonding and intermolecular π–π interactions to form loose molecular stacks. Interestingly, the unique molecular stacking structure provides a binding site and catalytic center for H₂O₂ that exhibits catalase-like activity, which can further ameliorate the efficiency of PDT and enhance the synergistic effect of PDT/PTT phototherapy in vitro and in vivo. This study can provide a simple but effective supramolecular strategy to design small molecule PSs with desirable aggregated structure for synergistic dual-mode phototherapy.     

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.     

The Art of Integrated Functionalization: Super Stable Black Phosphorus Achieved through Metal‐Organic Framework Coating

Black phosphorus (BP) is a promising 2D nanomaterial with a great potential in various areas, while its intrinsic instability greatly suppresses practical applications, particularly under harsh conditions (e.g., high temperature). Herein, BP functionalization with Al ion is achieved in an integrated manner through MIL‐53 metal‐organic framework (MOF) coating, which greatly improves both ambient and thermal stability of BP. For the obtained MIL‐53 coated BP (BP@MIL‐53), abundant Al ion within MIL‐53 interacts with the lone pair electrons of BP, and subsequently decreases the BP surface electron density, reducing the reactivity of BP toward O₂ and H₂O. The MOF growth crosslinks the Al ion on the BP surface, and achieves integrated functionalization to withstand the detachment of individual Al ion from the BP surface. The noncovalent bond of BP? Al and highly porous structure of MIL‐53 preserve the physical/chemical properties of BP to the maximum, and render BP@MIL‐53 with super‐stability. This functionalization strategy extends the applications of BP based devices under high temperature conditions. As a proof of concept, BP@MIL‐53 is further utilized as a NO₂ gas sensor under relatively high operating temperatures. The BP@MIL‐53 sensor exhibits fast response, outstanding selectivity, and high recovery dynamic process in contrast to bare BP sensor.     

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.     

In Situ Polymerized Hollow Mesoporous Organosilica Biocatalysis Nanoreactor for Enhancing ROS‐Mediated Anticancer Therapy

The combination of reactive oxygen species (ROS)‐involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhancing ROS‐mediated cancer treatment. Herein, an in situ polymerized hollow mesoporous organosilica nanoparticle (HMON) biocatalysis nanoreactor is reported to integrate the synergistic effect of PDT/CDT for enhancing ROS‐mediated pancreatic ductal adenocarcinoma treatment. 2‐(1‐hexyloxyethyl)‐2‐devinylpyropheophorbide‐a photosensitizer is hybridized within the framework of HMON via an “in situ framework growth” approach. Then, the hollow cavity of HMONs is exploited as a nanoreactor for “in situ polymerization” to synthesize the polymer containing thiol groups, thereby enabling the immobilization of ultrasmall gold nanoparticles, which behave like glucose oxidase‐like nanozyme, converting glucose into H₂O₂ to provide self‐supplied H₂O₂ for CDT. Meanwhile, Cu²⁺‐tannic acid complexes are further deposited on the surface of HMONs (HMON‐Au@Cu‐TA) to initiate Fenton‐like reaction to covert the self‐supplied H₂O₂ into ?OH, a highly toxic ROS. Finally, collagenase (Col), which can degrade the collagen I fiber in the extracellular matrix, is loaded into HMON‐Au@Cu‐TA to enhance the penetration of HMONs and O₂ infiltration for enhanced PDT. This study provides a good paradigm for enhancing ROS‐mediated antitumor efficacy. Meanwhile, this research offers a new method to broaden the application of silica based nanotheranostics.     

Hydrogen Selective NH2‐MIL‐53(Al) MOF Membranes with High Permeability

Hydrogen‐based energy is a promising renewable and clean resource. Thus, hydrogen selective microporous membranes with high performance and high stability are demanded. Novel NH₂‐MIL‐53(Al) membranes are evaluated for hydrogen separation for this goal. Continuous NH₂‐MIL‐53(Al) membranes have been prepared successfully on macroporous glass frit discs assisted with colloidal seeds. The gas sorption ability of NH₂‐MIL‐53(Al) materials is studied by gas adsorption measurement. The isosteric heats of adsorption in a sequence of CO₂ > N₂ > CH₄ ≈ H₂ indicates different interactions between NH₂‐MIL‐53(Al) framework and these gases. As‐prepared membranes are measured by single and binary gas permeation at different temperatures. The results of singe gas permeation show a decreasing permeance in an order of H₂ > CH₄ > N₂ > CO₂, suggesting that the diffusion and adsorption properties make significant contributions in the gas permeation through the membrane. In binary gas permeation, the NH₂‐MIL‐53(Al) membrane shows high selectivity for H₂ with separation factors of 20.7, 23.9 and 30.9 at room temperature (288 K) for H₂ over CH₄, N₂ and CO₂, respectively. In comparison to single gas permeation, a slightly higher separation factor is obtained due to the competitive adsorption effect between the gases in the porous MOF membrane. Additionally, the NH₂‐MIL‐53(Al) membrane exhibits very high permeance for H₂ in the mixtures separation (above 1.5 × 10^?6 mol m^?2 s^?1 Pa^?1) due to its large cavity, resulting in a very high separation power. The details of the temperature effect on the permeances of H₂ over other gases are investigated from 288 to 353 K. The supported NH₂‐MIL‐53(Al) membranes with high hydrogen separation power possess high stability, resistance to cracking, temperature cycling and show high reproducibility, necessary for the potential application to hydrogen recycling.     

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.     

Engineering Fe–Fe3C@Fe–N–C Active Sites and Hybrid Structures from Dual Metal–Organic Frameworks for Oxygen Reduction Reaction in H2–O2 Fuel Cell and Li–O2 Battery

Dual metal–organic frameworks (MOFs, i.e., MIL‐100(Fe) and ZIF‐8) are thermally converted into Fe–Fe₃C‐embedded Fe–N‐codoped carbon as platinum group metal (PGM)‐free oxygen reduction reaction (ORR) electrocatalysts. Pyrolysis enables imidazolate in ZIF‐8 rearranged into highly N‐doped carbon, while Fe from MIL‐100(Fe) into N‐ligated atomic sites concurrently with a few Fe–Fe₃C nanoparticles. Upon precise control of MOF compositions, the optimal catalyst is highly active for the ORR in half‐cells (0.88 V in base and 0.79 V versus RHE in acid in half‐wave potential), a proton exchange membrane fuel cell (0.76 W cm^?2 in peak power density) and an aprotic Li–O₂ battery (8749 mAh g^?1 in discharge capacity), representing a state‐of‐the‐art PGM‐free ORR catalyst. In the material, amorphous carbon with partial graphitization ensures high active site exposure and fast charge transfer simultaneously. Macropores facilitate mass transport to the catalyst surface, followed by oxygen penetration in micropores to reach the infiltrated active sites. Further modeling simulations shed light on the true Fe–Fe₃C contribution to the catalyst performance, suggesting Fe₃C enhances oxygen affinity, while metallic Fe promotes *OH desorption as the rate‐determining step at the nearby Fe–N–C sites. These findings demonstrate MOFs as model system for rational design of electrocatalyst for energy‐based functional applications.     

Tumor-Activated Photosensitization and Size Transformation of Nanodrugs

Effective intratumoral distribution of anticancer agents with good tumor penetration is of practical importance for photo-chemotherapy. Herein, a metal-organic framework (MOF) assisted strategy is reported for smart delivery of aggregation-induced emission photosensitizer (AIE PS) and chemodrug for deep tumor penetration to realize effective image-guided photo-chemotherapy. A newly designed AIE PS is loaded inside an iron(III) carboxylate-based MOF, MIL-100, to produce PS@MIL-100, which is encapsulated by doxorubicin (Dox) conjugated poly(ethylene glycol) methyl ether (PEG) to yield Dox-PEG-PS@MIL nanoparticles (NPs) with a diameter of 120 nm. After Dox-PEG-PS@MIL NPs reached the tumor site, intratumoral H₂O₂ can cause the release of the loaded PS at the tumor surface for activatable photodynamic therapy (PDT). The Dox-PEG segment is simultaneously triggered to self-assemble into ultrasmall Dox NPs. Under light irradiation, PDT is activated at the tumor surface, synergistically enhancing the tumor penetration of Dox NPs along with their ultrasmall size. After endocytosis of Dox NPs, free Dox is released from Dox NPs under low pH to enter cell nuclei for effective chemotherapy. Accompanied by bright far-red/near-infrared emission from the PS, image-guided photo-chemotherapy with enhanced efficacy is achieved.     

Molecular Engineering to Boost AIE‐Active Free Radical Photogenerators and Enable High‐Performance Photodynamic Therapy under Hypoxia

The severe hypoxia in solid tumors and the vicious aggregation‐caused fluorescence quenching (ACQ) of conventional photosensitizers (PSs) have limited the application of fluorescence imaging‐guided photodynamic therapy (PDT), although this therapy has obvious advantages in terms of its precise spatial–temporal control and noninvasive character. PSs featuring type I reactive oxygen species (ROS) based on free radicals and novel aggregation‐induced emission (AIE) characteristics (AIE‐PSs) could offer valuable opportunities to resolve the above problems, but molecular engineering methods are rare in previous reports. Herein, a strategy is proposed for generating stronger intramolecular charge transfer in electron‐rich anion‐π⁺ AIE‐active luminogens (AIEgens) to help suppress nonradiative internal conversion and to promote radiative and intersystem crossing to boost free radical generation. Systematic and detailed experimental and theoretical calculations prove the proposal herein: the electron‐donating abilities are enhanced in collaborative donors, and the AIE‐PSs exhibit higher performance in near‐infrared fluorescence imaging‐guided cancer PDT in vitro/vivo. This work serves as an important reference for the design of AIE‐active free radical generators to overcome the ACQ and tumor hypoxia challenges in PDT.     

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.     

NIR‐II Light Activated Photosensitizer with Aggregation‐Induced Emission for Precise and Efficient Two‐Photon Photodynamic Cancer Cell Ablation

Near infrared (NIR) light excitable photosensitizers are highly desirable for photodynamic therapy with deep penetration. Herein, a NIR‐II light (1200 nm) activated photosensitizer TQ‐BTPE is designed with aggregation‐induced singlet oxygen (¹O₂) generation for two‐photon photodynamic cancer cell ablation. TQ‐BTPE shows good two‐photon absorption and bright aggregation‐induced NIR‐I emission upon NIR‐II laser excitation. The ¹O₂ produced by TQ‐BTPE in an aqueous medium is much more efficient than that of commercial photosensitizer Ce6 under white light irradiation. Upon NIR‐II excitation, the two‐photon photosensitization of TQ‐BTPE is sevenfold higher than that of Ce6. The TQ‐BTPE molecules internalized by HeLa cells are mostly located in lysosomes as small aggregate dots with homogeneous distribution inside the cells, which favors efficient photodynamic cell ablation. The two‐photon photosensitization of TQ‐BTPE upon NIR‐I and NIR‐II excitation shows higher ¹O₂ generation efficiency than under NIR‐I excitation owing to the larger two‐photon absorption cross section at 920 nm. However, NIR‐II light exhibits better biological tissue penetration capability after passing through a fresh pork tissue, which facilitates stronger two‐photon photosensitization and better cancer cell ablation performance. This work highlights the promise of NIR‐II light excitable photosensitizers for deep‐tissue 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.     

Enzymatic Micromotors as a Mobile Photosensitizer Platform for Highly Efficient On‐Chip Targeted Antibacteria Photodynamic Therapy

Photodynamic therapy (PDT) functions when the light‐excited photosensitizers transfer energy to oxygen molecules (³O₂) to produce cytotoxic singlet oxygen (¹O₂) that can effectively kill cells or bacteria. However, the PDT efficacy is often reduced by the limited availability of ³O₂ surrounding the photosensitizer and extremely short diffusion range of the photoactivated ¹O₂. Herein, an enzymatic micromotor based on hollow mesoporous SiO₂ (mSiO₂) microspheres is constructed as a mobile and highly efficient photosensitizer platform. Carboxylated magnetic nanoparticles are connected with both hollow spheres and 5,10,15,20‐tetrakis(4‐aminophenyl)porphyrin molecules through covalent linkage between amino and carboxylic groups within a one‐step reaction. Due to the intrinsic asymmetry of the mSiO₂ spheres, the micromotors can be propelled by ionic diffusiophoresis induced by the enzymatic decomposition of urea. Via numerical simulation, the self‐propulsion mechanism is clarified and the movement direction is identified. By virtue of active self‐propulsion, the current system can overcome the long‐standing shortcomings of PDT and significantly enhance the PDT efficacy by improving the accessibility of the photosensitizer to ³O₂ and enlarging the diffusing range of ¹O₂. Therefore, by proposing a new solution to the bottleneck problems of PDT, this work provides insightful perspectives to the biomedical application of multifunctional micro/nanomotors.