Self-oxygenated co-assembled biomimetic nanoplatform for enhanced photodynamic therapy in hypoxic tumor

Photodynamic therapy (PDT) has shown great application potential in cancer treatment and the important manifestation of PDT in the inhibition of tumors is the activation of immunogenic cell death (ICD) effects. However, the strategy is limited in the innate hypoxic tumor microenvironment. There are two key elements for the realization of enhanced PDT: specific cellular uptake and release of the photosensitizer in the tumor, and a sufficient amount of oxygen to ensure photodynamic efficiency. Herein, self-oxygenated biomimetic nanoparticles (CS@M NPs) co-assembled by photosensitizer prodrug (Ce6-S-S-LA) and squalene (SQ) were engineered. In the treatment of triple negative breast cancer (TNBC), the oxygen carried by SQ can be converted to reactive oxygen species (ROS). Meanwhile, glutathione (GSH) consumption during transformation from Ce6-S-S-LA to chlorin e6 (Ce6) avoided the depletion of ROS. The co-assembled (CS NPs) were encapsulated by homologous tumor cell membrane to improve the tumor targeting. The results showed that the ICD effect of CS@M NPs was confirmed by the significant release of calreticulin (CRT) and high mobility group protein B1 (HMGB1), and it significantly activated the immune system by inhibiting the hypoxia inducible factor-1alpha (HIF-1α)-CD39-CD73-adenosine a2a receptor (A2AR) pathway, which not only promoted the maturation of dendritic cells (DC) and the presentation of tumor specific antigens, but also induced effective immune infiltration of tumors. Overall, the integrated nanoplatform implements the concept of multiple advantages of tumor targeting, reactive drug release, and synergistic photodynamic therapy-immunotherapy, which can achieve nearly 90% tumor suppression rate in orthotopic TNBC models.     

H2S‐Activable MOF Nanoparticle Photosensitizer for Effective Photodynamic Therapy against Cancer with Controllable Singlet‐Oxygen Release

Photodynamic therapy (PDT) has emerged as an important minimally invasive tumor treatment technology. The search for an effective photosensitizer to realize selective cancer treatment has become one of the major foci in recent developments of PDT technology. Controllable singlet‐oxygen release based on specific cancer‐associated events, as another major layer of selectivity mode, has attracted great attention in recent years. Here, for the first time, we demonstrated that a novel mixed‐metal metal–organic framework nanoparticle (MOF NP) photosensitizer can be activated by a hydrogen sulfide (H₂S) signaling molecule in a specific tumor microenvironment for PDT against cancer with controllable singlet‐oxygen release in living cells. The effective removal of tumors in vivo further confirmed the satisfactory treatment effect of the MOF NP photosensitizer.     

Tumor Microenvironment Stimuli-Responsive Fluorescence Imaging and Synergistic Cancer Therapy by Carbon-Dot–Cu2+ Nanoassemblies

A method is developed to fabricate tumor microenvironment (TME) stimuli-responsive nanoplatform for fluorescence (FL) imaging and synergistic cancer therapy via assembling photosensitizer (chlorine e6, Ce6) modified carbon dots (CDs-Ce6) and Cu²⁺. The as-obtained nanoassemblies (named Cu/CC nanoparticles, NPs) exhibit quenched FL and photosensitization due to the aggregation of CDs-Ce6. Their FL imaging and photodynamic therapy (PDT) functions are recovered efficiently once they entering tumor sites by the stimulation of TME. Introducing of Cu²⁺ not only provides extra chemodynamic therapy (CDT) function through reaction with hydrogen peroxide (H₂O₂), but also depletes GSH in tumors by a redox reaction, thus amplifying the intracellular oxidative stress and enhancing the efficacy of reactive oxygen species (ROS) based therapy. Cu/CC NPs can act as a FL imaging guided trimodal synergistic cancer treatment agent by photothermal therapy (PTT), PDT, and thermally amplified CDT.     

GSH and H2O2 Co‐Activatable Mitochondria‐Targeted Photodynamic Therapy under Normoxia and Hypoxia

Currently, photosensitizers (PSs) that are microenvironment responsive and hypoxia active are scarcely available and urgently desired for antitumor photodynamic therapy (PDT). Presented herein is the design of a redox stimuli activatable metal‐free photosensitizer (aPS), also functioning as a pre‐photosensitizer as it is converted to a PS by the mutual presence of glutathione (GSH) and hydrogen peroxide (H₂O₂) with high specificity on a basis of domino reactions on the benzothiadiazole ring. Superior to traditional PSs, the activated aPS contributed to efficient generation of reactive oxygen species including singlet oxygen and superoxide ion through both type 1 and type 2 pathways, alleviating the aerobic requirement for PDT. Equipped with a triphenylphosphine ligand for mitochondria targeting, ^mito aPS showed excellent phototoxicity to tumor cells with low light fluence under both normoxic and hypoxic conditions, after activation by intracellular GSH and H₂O₂. The ^mito aPS was also compatible to near infrared PDT with two photon excitation (800 nm) for extensive bioapplications.     

Co-delivery of enzymes and photosensitizers via metal-phenolic network capsules for enhanced photodynamic therapy

The intrinsic hypoxic tumor microenvironment and limited accumulation of photosensitizers（PSs） result in unsatisfied efficiency of photodynamic therapy（PDT）.To enhance the PDT efficiency against solid tumors,a functional oxygen self-supplying and PS-delivering nanosystem is fabricated via the combination of catalase（CAT）,chlorin e6（Ce6） and metal-phenolic network（MPN） capsule.It is demonstrated that the CAT encapsulated in the capsules（named CCM capsules） could catalyze the degradation of hydrog...     

A BODIPY-modified polymeric micelle for sustaining enhanced photodynamic therapy

Photodynamic therapy（PDT） has been gaining popularity in both scientific research and clinic applications due to its non-invasiveness and spatiotemporal targeting properties. Nevertheless, the local hypoxic microenvironment in tumor tissue impedes PDT universality. To overcome this drawback, a 2-pyridonebearing BODIPY photosensitizer was synthesized rationally and introduced to polyethyleneglycol-bpoly（aspartic acid） to form a photosensitizer-¹O₂ generation, storage/release...     

A Smart Photosensitizer–Manganese Dioxide Nanosystem for Enhanced Photodynamic Therapy by Reducing Glutathione Levels in Cancer Cells

Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species to kill cancer cells. However, a high concentration of glutathione (GSH) is present in cancer cells and can consume reactive oxygen species. To address this problem, we report the development of a photosensitizer–MnO₂ nanosystem for highly efficient PDT. In our design, MnO₂ nanosheets adsorb photosensitizer chlorin e6 (Ce6), protect it from self‐destruction upon light irradiation, and efficiently deliver it into cells. The nanosystem also inhibits extracellular singlet oxygen generation by Ce6, leading to fewer side effects. Once endocytosed, the MnO₂ nanosheets are reduced by intracellular GSH. As a result, the nanosystem is disintegrated, simultaneously releasing Ce6 and decreasing the level of GSH for highly efficient PDT. Moreover, fluorescence recovery, accompanied by the dissolution of MnO₂ nanosheets, can provide a fluorescence signal for monitoring the efficacy of delivery.     

Hybrid TiO2–Ruthenium Nano‐photosensitizer Synergistically Produces Reactive Oxygen Species in both Hypoxic and Normoxic Conditions

Photodynamic therapy (PDT) is widely used to treat diverse diseases, but its dependence on oxygen to produce cytotoxic reactive oxygen species (ROS) diminishes the therapeutic effect in a hypoxic environment, such as solid tumors. Herein, we developed a ROS‐producing hybrid nanoparticle‐based photosensitizer capable of maintaining high levels of ROS under both normoxic and hypoxic conditions. Conjugation of a ruthenium complex (N3) to a TiO₂ nanoparticle afforded TiO₂‐N3. Upon exposure of TiO₂‐N3 to light, the N3 injected electrons into TiO₂ to produce three‐ and four‐fold more hydroxyl radicals and hydrogen peroxide, respectively, than TiO₂ at 160 mmHg. TiO₂‐N3 maintained three‐fold higher hydroxyl radicals than TiO₂ under hypoxic conditions via N3‐facilitated electron–hole reduction of adsorbed water molecules. The incorporation of N3 transformed TiO₂ from a dual type I and II PDT agent to a predominantly type I photosensitizer, irrespective of the oxygen content.     

GSH and H2O2 Co-Activatable Mitochondria-Targeted Photodynamic Therapy under Normoxia and Hypoxia

Currently, photosensitizers (PSs) that are microenvironment responsive and hypoxia active are scarcely available and urgently desired for antitumor photodynamic therapy (PDT). Presented herein is the design of a redox stimuli activatable metal-free photosensitizer (aPS), also functioning as a pre-photosensitizer as it is converted to a PS by the mutual presence of glutathione (GSH) and hydrogen peroxide (H₂O₂) with high specificity on a basis of domino reactions on the benzothiadiazole ring. Superior to traditional PSs, the activated aPS contributed to efficient generation of reactive oxygen species including singlet oxygen and superoxide ion through both type 1 and type 2 pathways, alleviating the aerobic requirement for PDT. Equipped with a triphenylphosphine ligand for mitochondria targeting, ^mito aPS showed excellent phototoxicity to tumor cells with low light fluence under both normoxic and hypoxic conditions, after activation by intracellular GSH and H₂O₂. The ^mito aPS was also compatible to near infrared PDT with two photon excitation (800 nm) for extensive bioapplications.     

A Phototheranostic Strategy to Continuously Deliver Singlet Oxygen in the Dark and Hypoxic Tumor Microenvironment

Continuous irradiation during photodynamic therapy (PDT) inevitably induces tumor hypoxia, thereby weakening the PDT effect. In PDT‐induced hypoxia, providing singlet oxygen from stored chemical energy may enhance the cell‐killing effect and boost the therapeutic effect. Herein, we present a phototheranostic (DPPTPE@PEG‐Py NPs) prepared by using a 2‐pyridone‐based diblock polymer (PEG‐Py) to encapsulate a semiconducting, heavy‐atom‐free pyrrolopyrrolidone‐tetraphenylethylene (DPPTPE) with high singlet‐oxygen‐generation ability both in dichloromethane and water. The PEG‐Py can trap the ¹O₂ generated from DPPTPE under laser irradiation and form a stable intermediate of endoperoxide, which can then release ¹O₂ in the dark, hypoxic tumor microenvironment. Furthermore, fluorescence‐imaging‐guided phototherapy demonstrates that this phototheranostic could completely inhibit tumor growth with the help of laser irradiation.     

Tumor microenvironment-responsive MnSiO3-Pt@BSA-Ce6 nanoplatform for synergistic catalysis-enhanced sonodynamic and chemodynamic cancer therapy

Compared with traditional photodynamic therapy （PDT）,ultrasound （US） triggered sonodynamic therapy （SDT） has a wide application prospect in tumor therapy because of its deeper penetration depth.Herein,a novel MnSiO₃-Pt （MP） nanocomposite composed of Mn Si O₃nanosphere and noble metallic Pt was successfully constructed.After modification with bovine serum albumin （BSA） and chlorine e6 （Ce6）,the multifunctional nanoplatform Mn Si O₃-Pt@BSA-Ce6 （MPBC） realized the m...     

Spatiotemporally controlled O2 and singlet oxygen self-sufficient nanophotosensitizers enable the in vivo high-yield synthesis of drugs and efficient hypoxic tumor therapy

Carrying out the in vivo syntheses of drugs toxic to tumors based on the specific features of the tumor microenvironment is critical for ensuring specific antitumor efficacy. However, achieving in situ high-yield synthetic toxic drugs from non-toxic agents and reducing their drug resistance in hypoxic tumors remain challenges. Herein we created a tumor-microenvironment-responsive porous Pt/Pt(iv) methylene blue coordination polymer nanoshuttle (Pt/PtMBCPNS) photosensitizer with spatiotemporally controlled O₂ and singlet oxygen (¹O₂) self-sufficient for the in vivo high-yield synthesis of drugs and efficient hypoxic tumor therapy. After being endocytosed, the nanophotosensitizer as a cascade catalyst was observed to effectively catalyze the conversion of endogenous H₂O₂ to O₂, and was hence found to play a dual role in the enhanced tumor therapy. PtMBCPNSs, upon being irradiated with red light, efficiently converted O₂ into ¹O₂. Subsequently, ¹O₂ oxidized non-toxic 1,5-dihydroxynaphthalene to form the anticancer agent juglone with a high yield. In addition, O₂ was found to be able to improve the hypoxic microenvironment without light irradiation, thus enhancing the antitumor efficacy of the produced drugs and reducing drug resistance. As a result, by enhancing the synergistic effect of the treatment, this nanophotosensitizer significantly inhibited the growth of tumors and avoided damage to normal tissues/organs. Collectively, this work highlights a robust nanoplatform with the spatiotemporally controlled in vivo high-yield synthesis of drugs and generation of O₂ to help overcome the current limitations of chemical-based therapies against hypoxic tumors.

A porous photosensitizer displaying catalase-like activity and drug synthesis ability was synthesized for the synergistic chemo-photodynamic therapy, opening new promising ways for carrying out the precise cooperative treatment of hypoxic tumors.     

A Smart DNAzyme–MnO2 Nanosystem for Efficient Gene Silencing

DNAzymes hold promise for gene‐silencing therapy, but the lack of sufficient cofactors in the cell cytoplasm, poor membrane permeability, and poor biostability have limited the use of DNAzymes in therapeutics. We report a DNAzyme–MnO₂ nanosystem for gene‐silencing therapy. MnO₂ nanosheets adsorb chlorin e6‐labelled DNAzymes (Ce6), protect them from enzymatic digestion, and efficiently deliver them into cells. The nanosystem can also inhibit ¹O₂ generation by Ce6 in the circulatory system. In the presence of intracellular glutathione (GSH), MnO₂ is reduced to Mn²⁺ ions, which serve as cofactors of 10–23 DNAzyme for gene silencing. The release of Ce6 generates ¹O₂ for more efficient photodynamic therapy. The Mn²⁺ ions also enhance magnetic resonance contrast, providing GSH‐activated magnetic resonance imaging (MRI) of tumor cells. The integration of fluorescence recovery and MRI activation provides fluorescence/MRI bimodality for monitoring the delivery of DNAzymes.     

Photosynthetic Tumor Oxygenation by Photosensitizer‐Containing Cyanobacteria for Enhanced Photodynamic Therapy

Sustained tumor oxygenation is of critical importance during type‐II photodynamic therapy (PDT), which depends on the intratumoral oxygen level for the generation of reactive oxygen species. Herein, the modification of photosynthetic cyanobacteria with the photosensitizer chlorin e6 (ce6) to form ce6‐integrated photosensitive cells, termed ceCyan, is reported. Upon 660 nm laser irradiation, sustained photosynthetic O₂ evolution by the cyanobacteria and the immediate generation of reactive singlet oxygen species (¹O₂) by the integrated photosensitizer could be almost simultaneously achieved for tumor therapy using type‐II PDT both in vitro and in vivo. This work contributes a conceptual while practical paradigm for biocompatible and effective PDT using hybrid microorganisms, displaying a bright future in clinical PDT by microbiotic nanomedicine.     

Activatable Type I Photosensitizer with Quenched Photosensitization Pre and Post Photodynamic Therapy

The phototoxicity of photosensitizers (PSs) pre and post photodynamic therapy (PDT), and the hypoxic tumor microenvironment are two major problems limiting the application of PDT. While activatable PSs can successfully address the PS phototoxicity pre PDT, and type I PS can generate reactive oxygen species (ROS) effectively in hypoxic environment, very limited approaches are available for addressing the phototoxicity post PDT. There is virtually no solution available to address all these issues using a single design. Herein, we propose a proof-of-concept on-demand switchable photosensitizer with quenched photosensitization pre and post PDT, which could be activated only in tumor hypoxic environment. Particularly, a hypoxia-normoxia cycling responsive type I PS TPFN-AzoCF₃ was designed to demonstrate the concept, which was further formulated into TPFN-AzoCF₃ nanoparticles (NPs) using DSPE-PEG-2000 as the encapsulation matrix. The NPs could be activated only in hypoxic tumors to generate type I ROS during PDT treatment, but remain non-toxic in normal tissues, pre or after PDT, thus minimizing side effects and improving the therapeutic effect. With promising results in in vitro and in vivo tumor treatment, this presented strategy will pave the way for the design of more on-demand switchable photosensitizers with minimized side effects in the future.     

Deciphering Oxygen-Independent Augmented Photodynamic Oncotherapy by Facilitating the Separation of Electron-Hole Pairs

Developing Type-I photosensitizers provides an attractive approach to solve the dilemma of inadequate efficacy of photodynamic therapy (PDT) caused by the inherent oxygen consumption of traditional Type-II PDT and anoxic tumor microenvironment. The challenge for the exploration of Type-I PSs is to facilitate the electron transfer ability of photosensitization molecules for transforming oxygen or H₂O to reactive oxygen species (ROS). Herein, we propose an electronic acceptor-triggered photoinduced electron transfer (a-PET) strategy promoting the separation of electron-hole pairs by marriage of two organic semiconducting molecules of a non-fullerene scaffold-based photosensitizer and a perylene diimide that significantly boost the Type-I PDT pathway to produce plentiful ROS, especially, inducing 3.5-fold and 2.5-fold amplification of hydroxyl (OH⋅) and superoxide (O₂⁻⋅) generation. Systematic mechanism exploration reveals that intermolecular electron transfer and intramolecular charge separation after photoirradiation generate a competent production of radical ion pairs that promote the Type-I PDT process by theoretical calculation and ultrafast femtosecond transient absorption (fs-TA) spectroscopy. By complementary tumor diagnosis with photoacoustic imaging and second near-infrared fluorescence imaging, this as-prepared nanoplatform exhibits fabulous photocytotoxicity in harsh hypoxic conditions and terrific cancer revoked abilities in living mice. We envision that this work will broaden the insight into high-efficiency Type-I PDT for cancer phototheranostics.     

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored,Activatable Cancer Chemotherapy

The development of biodegradable inorganic nanoparticles with a tumor microenvironment‐activated therapeutic mode of action is urgently needed for precision cancer medicine. Herein, the synthesis of ultrathin lanthanide nanoscrolls (Gd₂O₃ NSs) is reported, which biodegrade upon encountering the tumor microenvironment. The Gd₂O₃ NSs showed highly controlled magnetic properties, which enabled their high‐resolution magnetic resonance imaging (MRI). Importantly, Gd₂O₃ NSs degrade in a pH‐responsive manner and selectively penetrate tumor tissue, enabling the targeted release of anti‐cancer drugs. Gd₂O₃ NSs can be efficiently loaded with an anti‐cancer drug (DOX, 80 %) and significantly inhibit tumor growth with negligible cellular and tissue toxicity both in vitro and in vivo. This study may provide a novel strategy to design tumor microenvironment‐responsive inorganic nanomaterials for biocompatible bioimaging and biodegradation‐enhanced cancer therapy.     

A Multiresponsive Nanohybrid to Enhance the Lysosomal Delivery of Oxygen and Photosensitizers

Photodynamic therapy (PDT) is a promising cancer ablation method, but its efficiency is easily affected by several factors, such as the insufficient delivery of photosensitizers, low oxygen levels as well as long distance between singlet oxygen and intended organelles. A multifunctional nanohybrid, named MGAB, consisting of gelatin-coated manganese dioxide and albumin-coated gold nanoclusters, was designed to overcome these issues by improving chlorin e6 (Ce6) delivery and stimulating oxygen production in lysosomes. MGAB were quickly degraded in a high hydrogen peroxide, high protease activity, and low pH microenvironment, which is closely associated with tumor growth. The Ce6-loaded MGAB were picked up by tumor cells through endocytosis, degraded within the lysosomes, and released oxygen and photosensitizers. Upon near-infrared light irradiation, the close proximity of oxygen with photosensitizer within lysosomes enabled the production of cytotoxic singlet oxygen, resulting in more effective PDT.     

Calcium Phosphate‐Reinforced Photosensitizer‐Loaded Polymer Nanoparticles for Photodynamic Therapy

Calcium phosphate‐reinforced photosensitizer‐loaded polymer nanoparticles have been developed for photodynamic therapy. Chlorin e6 (Ce6)‐loaded core–shell–corona polymer micelles of poly(ethylene glycol)‐b‐poly(L ‐aspartic acid)‐b‐poly(L ‐phenylalanine) ( PEG-PAsp-PPhe ) were employed as template nanoparticles for mineralization with calcium phosphate (CaP). CaP deposition was performed by the electrostatic localization of calcium ions at the anionic PAsp middle shells and the subsequent addition of phosphate anions. CaP‐reinforced nanoparticles exhibited enhanced stability. The CaP mineral layer effectively inhibited Ce6 release from the Ce6‐loaded mineralized nanoparticles (Ce6‐NP‐CaP) at physiological pH value. At an acidic endosomal pH value of 5.0, Ce6 release was enhanced, owing to rapid dissolution of the CaP minerals. Upon irradiation of Ce6‐NP‐CaP‐treated MCF‐7 breast‐tumor cells, the cell viability dramatically decreased with increasing irradiation time. The phototoxicity of Ce6‐NP‐CaP was much higher than that of free Ce6. Non‐invasive optical‐imaging results indicated that Ce6‐NP‐CaP exhibited enhanced tumor specificity compared with free Ce6 and Ce6‐loaded non‐mineralized polymer nanoparticles (Ce6‐NP).     

An Endoplasmic Reticulum Targeting Type I Photosensitizer for Effective Photodynamic Therapy against Hypoxic Tumor Cells

Organelle-targeted type I photodynamic therapy (PDT) shows great potential to overcome the hypoxic microenvironment in solid tumors. The endoplasmic reticulum (ER) is an indispensable organelle in cells with important biological functions. When the ER is damaged due to the production of reactive oxygen species (ROS), the accumulation of misfolded proteins will interfere with ER homeostasis, resulting in ER stress. Here, an ER-targeted benzophenothiazine-based photosensitizer NBS-ER was presented. ER targeting modification significantly reduced the dark toxicity and improved phototoxicity index (PI). NBS-ER could effectively produce O₂⁻⋅ with near-infrared irradiation, making its phototoxicity under hypoxia close to that under normoxia. Meanwhile, the photoinduced ROS triggered ER stress and induced apoptosis. In addition, NBS-ER possessed excellent photodynamic therapeutic effect in 4T1-tumor-bearing mice.