Precision photothermal therapy and photoacoustic imaging by in situ activatable thermoplasmonics

Phototherapy holds great promise for disease treatment; however, traditional “always-on” photoagents have been restricted to clinical translation due to their nonspecific response and side effects on normal tissues. Here, we show a tumor microenvironment activated photothermal and photoacoustic agent as an activatable prodrug and probe that allows precise cancer diagnosis and treatment. Such an in situ revitalized therapeutic and contrast agent is achieved via controllable plasmonic heating for thermoplasmonic activation. This enables monitoring of signal molecule dynamics, real-time photothermal and photoacoustic imaging of tumors and lymph node metastasis, and targeted photothermal therapy without unwanted phototoxicity to normal tissues. Our study provides a practical solution to the non-specificity problem in phototherapy and offers precision cancer therapeutic and theranostic strategies. This work may advance the development of ultrasensitive disease diagnosis and precision medicine.

A tumor microenvironment-activated photoagent is reported for precise photothermal therapy and photoacoustic imaging via controllable thermoplasmonics. The agent can sensitively image tumors and lymph node metastasis and specifically ablate tumors.     

Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis

Cancer cells are vulnerable to reactive oxygen species (ROS) due to their abnormal redox environment. Accordingly, combination of chemotherapy and oxidative stress has gained increasing interest for the treatment of cancer. We report a novel seleno-prodrug of gemcitabine (Gem), Se–Gem, and evaluated its activation and biological effects in cancer cells. Se–Gem was prepared by introducing a 1,2-diselenolane (a five-membered cyclic diselenide) moiety into the parent drug Gemvia a carbamate linker. Se–Gem is preferably activated by glutathione (GSH) and displays a remarkably higher potency than Gem (up to a 6-fold increase) to a panel of cancer cell lines. The activation of Se–Gem by GSH releases Gem and a seleno-intermediate nearly quantitatively. Unlike the most ignored side products in prodrug activation, the seleno-intermediate further catalyzes a conversion of GSH and oxygen to GSSG (oxidized GSH) and ROS via redox cycling reactions. Thus Se–Gem may be considered as a suicide agent to deplete GSH and works by a combination of chemotherapy and oxidative stress. This is the first case that employs a cyclic diselenide in prodrug design, and the success of Se–Gem as well as its well-defined action mechanism demonstrates that the 1,2-diselenolane moiety may serve as a general scaffold to advance constructing novel therapeutic molecules with improved potency via a combination of chemotherapy and oxidative stress.

The 1,2-diselenolane unit is a general scaffold to construct glutathione-dependent prodrugs that show increased potency to cancer cells, and work via a combination of chemotherapy and oxidative stress.     

A pH reversibly activatable NIR photothermal/photodynamic-in-one agent integrated with renewable nanoimplants for image-guided precision phototherapy

Phototherapy has great potential to revolutionize conventional therapeutic modalities. However, most phototherapeutic strategies based on multicomponent therapeutic agents generally lack tumor-specificity, resulting in asynchronous therapy and superimposed side-effects. Severe heat damage is also inevitable because of the necessity of continuous external irradiation. Here we show the design of an acid-activated and continuous external irradiation-free photothermal and photodynamic (PTT/PDT) synchronous theranostic nanoplatform for precision tumor-targeting near-infrared (NIR) image-guided therapy. pH-reversibly responsive brominated asymmetric cyanine is designed as the tumor-specific NIR PTT/PDT-in-one agent to enhance anticancer efficiency and reduce side-effects. Ultra-small NIR persistent luminescence nanoparticles are prepared as both the imaging unit and renewable nanoimplant. Biotin functionalized polyethylene glycol is introduced to endow active tumor-targeting ability and prolong blood-circulation. The developed smart platform offers merits of reversible activation, PTT/PDT synergetic enhancement, tumor targetability and continuous external irradiation-free properties, allowing autofluorescence-free image-guided phototherapy only in tumor sites. This work paves the way to developing smart theranostic nanoplatforms for precision medicine.

A smart NIR photothermal/photodynamic-in-one agent integrated with renewable nanoimplants for autofluorescence- and continuous external irradiation-free image-guided precision tumor-targeting phototherapy.     

An azo dye for photodynamic therapy that is activated selectively by two-photon excitation

Two-photon photodynamic therapy (TP-PDT) is a promising approach for the treatment of cancer because of its better penetration depth and superior spatial selectivity. Here, we describe an azo group containing cyclized-cyanine derivatives (ACC1 and ACC2) as a two-photon activated, type I based photosensitizer (PS). These small-molecule and heavy atom-free organic dyes showed marked reactive oxygen species (ROS)-generating ability under physiological conditions, as well as fast loading ability into the cells and negligible dark toxicity. Live cell analyses with one- and two-photon microscopy revealed that these dyes showed higher ROS generation ability upon two-photon excitation than upon one-photon excitation via the type I process. The PSs have superior PDT properties compared to conventional Visudyne and 5-ALA under mild conditions. These characteristics allowed for precise PDT at the target region in mimic tumor spheroids, demonstrating that the developed TP PS could be useful in efficient PDT applications and in designing various PSs.

Azo containing dyes as a two-photon selective and type I based photosensitizers (PSs) were developed that exhibit excellent photodynamic therapy properties under mild condition.     

Designing a highly stable coordination-driven metallacycle for imaging-guided photodynamic cancer theranostics

Coordination-driven self-assembly features good predictability and directionality in the construction of discrete metallacycles and metallacages with well-defined sizes and shapes, but their medicinal application has been limited by their low stability and solubility. Herein, we have designed and synthesized a highly stable coordination-driven metallacycle with desired functionality derived from a perylene-diimide ligand via a spontaneous deprotonation self-assembly process. Brilliant chemical stability and singlet oxygen production ability of this emissive octanuclear organopalladium macrocycle make it a good candidate toward biological studies. After cellular uptake by endocytosis, the metallacycle exhibits potent fluorescence cell imaging properties and cancer photodynamic therapeutic ability through enhancing ROS production, with high biocompatibility and safety. This study not only provides a rational design strategy for highly stable luminescent organopalladium metallacycles, but also sheds light on their application in imaging-guided photodynamic cancer therapy.

A highly-luminescent metallacycle with chemical stability and singlet oxygen production ability were obtained by a spontaneous deprotonation self-assembly process, which exhibits application potential in imaging-guided photodynamic cancer therapy.     

In vivo therapeutic response monitoring by a self-reporting upconverting covalent organic framework nanoplatform

The real-time and in situ monitoring of reactive oxygen species (ROS) generation is critical for minimizing the nonspecific damage derived from the high doses of ROS required during the photodynamic therapy (PDT) process. However, phototherapeutic agents that can generate ROS-related imaging signals during PDT are rare, hampering the facile prediction of the future therapeutic outcome. Herein, we develop an upconverting covalent organic framework (COF) nanoplatform via a core-mediated strategy and further functionalized it with a singlet oxygen reporter for the efficient near-infrared activated and in situ self-reporting of PDT. In this work, the COF photodynamic efficacy is greatly improved (12.5 times that of irregular COFs) via tailoring the size. Furthermore, this nanoplatform is able to not only produce singlet oxygen for PDT, but it can also emit singlet oxygen-correlated luminescence, allowing the real-time and in situ monitoring of the therapeutic process for cancer cells or solid tumors in vivo via near-infrared luminescence imaging. Thus, our core-mediated synthetic and size-tailored strategy endows the upconverting COF nanoplatform with promising abilities for high-efficacy, deep-tissue, precise photodynamic treatment.

An upconverting covalent organic framework nanoplatform is designed for the first time for the near-infrared activated in situ self-reporting of photodynamic therapy in vivo.     

A J-aggregated nanoporphyrin overcoming phototoxic side effects in superior phototherapy with two-pronged effects

Phototherapy has been a promising therapeutic modality for pathological tissue due to its spatiotemporal selectivity and non-invasive characteristics. However, as a core component of phototherapy, a single photosensitizer (PS) nanoplatform integrating excellent therapeutic efficiency and minimal side effects remains an urgent but unmet need. Here, we construct a J-aggregated nano-porphyrin termed MTE based on the self-assembly of methyl-pheophorbide a derivative MPa-TEG (MT) and natural polyphenolic compound epigallocatechin gallate (EGCG). Due to the synergistic interaction between similar large π-conjugated structural EGCG and MT, MTE with small and uniform size is obtained by effectively hindering Ostwald ripening of MT. Noteworthily, MTE not only effectively avoids the inadvertent side effects of phototoxicity during transport thank to the ability of reactive oxygen species (ROS) scavenging, but also achieves two-pathway augmented superior phototherapy: (1) enhancing photodynamic therapy (PDT) via inhibiting the expression of anti-apoptosis protein surviving; (2) achieving adjuvant mild-temperature laser interstitial thermal therapy (LITT) via reducing the tumor thermoresistance on account that MTE inhibits the overexpression of HSP 70 and HSP 90. This research not only offers a facile strategy to construct multicomponent nanoplatforms but also provides a new pathway for efficient and low-toxicity phototherapy, which is beneficial to the future clinical application.

J-aggregated nanoporphyrin (MTE) integrates minimal side effects and two-pathway augmented superior phototherapy: enhancing photodynamic therapy (PDT) and achieving adjuvant mild-temperature laser interstitial thermal therapy (LITT).     

Single-molecule photosensitizers for NIR-II fluorescence and photoacoustic imaging guided precise anticancer phototherapy

It is ideal yet challenging to achieve precise tumor targeting and high-quality imaging guided combined photodynamic and photothermal therapy (PDT and PTT). In this study, we synthesized a series of D–π–A-type single-molecule photosensitizers (CyE-TT, CyQN-TT, and CyQN-BTT) based on quaternized 1,1,2-trimethyl-1H-benz[e]indoles as acceptors by introducing π-bridges to elongate their emission wavelength and triphenylamine as a donor to construct a twisted molecular conformation. We found that the ¹O₂ generation ability and the photothermal conversion efficiency (PCE) are directly correlated with the π-bridge between donors and acceptors in these molecules. When a 2,1,3-benzothiadiazole group as a π-bridge was introduced into CyQN-BTT, the singlet oxygen yield enhanced to 27.1%, PCE to 37.8%, and the emission wavelength was red-shifted to near-infrared II (NIR-II). Importantly, double-cationic CyQN-BTT displays structure-inherent cancer cell targeting ability instead of targeting normal cells. Consequently, relying on NIR-II fluorescence imaging (NIR-II FLI) and photoacoustic imaging (PAI) guided PDT and PTT, CyQN-BTT can accurately locate solid tumors in mice and effectively eliminate them with good biocompatibility and biosafety to normal tissues. This study provides insights into the design and development of a tumor-specific targeting multifunctional photosensitizer for precise cancer phototherapy.

An D–π–A-type single-molecule photosensitizer with structure-inherent cancer cell targeting ability was developed for NIR-II fluorescence imaging and photoacoustic imaging guided phototherapy to effectively eliminate tumors in mice.     

Supramolecular agents for combination of photodynamic therapy and other treatments

Photodynamic therapy (PDT) is a promising treatment for cancers such as superficial skin cancers, esophageal cancer, and cervical cancer. Unfortunately, PDT often does not have sufficient therapeutic benefits due to its intrinsic oxygen dependence and the limited permeability of irradiating light. Side effects from “always on” photosensitizers (PSs) can be problematic, and PDT cannot treat tumor metastases or recurrences. In recent years, supramolecular approaches using non-covalent interactions have attracted attention due to their potential in PS development. A supramolecular PS assembly could be built to maximize photodynamic effects and minimize side effects. A combination of two or more therapies can effectively address shortcomings while maximizing the benefits of each treatment regimen. Using the supramolecular assembly, it is possible to design a multifunctional supramolecular PS to exert synergistic effects by combining PDT with other treatment methods. This review provides a summary of important research progress on supramolecular systems that can be used to combine PDT with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT, and it provides an overview of the prospects for future cancer treatment advances and clinical applications.

This review provides a summary of important research progress on supramolecular systems that can be used to combine photodynamic therapy (PDT) with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT.     

A light-controlled multi-step drug release nanosystem targeting tumor hypoxia for synergistic cancer therapy

Hypoxia is a major obstacle for cancer therapy due to its association with cell proliferation, tumor distant metastasis, and treatment resistance. In this study, a hypoxia-activated bifunctional prodrug (CC5) was designed, synthesized and encapsulated by a photo-responsive ruthenium complex-derived polymer to yield a light-controlled multi-step drug release system (CC5-RuCa) for synergistic therapy against tumor hypoxia. Under NIR irradiation, CC5-RuCa not only generated ROS to kill the cancer cells in the exterior of the tumor but also released the prodrug CC5 with enhanced intratumoral penetration in the severe hypoxia region inside the tumor tissue. In vivo studies on MDA-MB-231 xenograft models revealed that CC5-RuCa with preferential accumulation in the tumor exhibited highly efficient tumor regression through the synergistic effect of photodynamic therapy and hypoxia-activated chemotherapy.

A photo-responsive ruthenium complex-derived micelle (CC5-RuCa) loaded with CC5 was prepared for light and tumor microenvironment-controlled multistage drug-release.     

Dual-targeted photothermal agents for enhanced cancer therapy

Photothermal therapy, in which light is converted into heat and triggers local hyperthermia to ablate tumors, presents an inherently specific and noninvasive treatment for tumor tissues. In this area, the development of efficient photothermal agents (PTAs) has always been a central topic. Although many efforts have been made on the investigation of novel molecular architectures and photothermal materials over the past decades, PTAs can cause severe damage to normal tissues because of the poor tumor aggregate ability and high irradiation density. Recently, dual-targeted photothermal agents (DTPTAs) provide an attractive strategy to overcome these problems and enhance cancer therapy. DTPTAs are functionalized with two classes of targeting units, including tumor environment targeting sites, tumor targeting sites and organelle targeting sites. In this perspective, typical targeted ligands and representative examples of photothermal therapeutic agents with dual-targeted properties are systematically summarized and recent advances using DTPTAs in tumor therapy are highlighted.

In this perspective, the design, applications and potential directions of photothermal therapeutic agents with dual-targeted properties are systematically described.     

Copper-assisted oxidation of catechols into quinone derivatives

Catechols are ubiquitous substances often acting as antioxidants, thus of importance in a variety of biological processes. The Fenton and Haber–Weiss processes are thought to transform these molecules into aggressive reactive oxygen species (ROS), a source of oxidative stress and possibly inducing degenerative diseases. Here, using model conditions (ultrahigh vacuum and single crystals), we unveil another process capable of converting catechols into ROSs, namely an intramolecular redox reaction catalysed by a Cu surface. We focus on a tri-catechol, the hexahydroxytriphenylene molecule, and show that this antioxidant is thereby transformed into a semiquinone, as an intermediate product, and then into an even stronger oxidant, a quinone, as final product. We argue that the transformations occur via two intramolecular redox reactions: since the Cu surface cannot oxidise the molecules, the starting catechol and the semiquinone forms each are, at the same time, self-oxidised and self-reduced. Thanks to these reactions, the quinone and semiquinone are able to interact with the substrate by readily accepting electrons donated by the substrate. Our combined experimental surface science and ab initio analysis highlights the key role played by metal nanoparticles in the development of degenerative diseases.

An antioxidant catechol transforms following intramolecular redox reactions into highly reactive oxygen species, a semiquinone and a quinone, on copper.     

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.     

Type I macrophage activator photosensitizer against hypoxic tumors

Photodynamic immunotherapy has emerged as a promising strategy to treat cancer. However, the hypoxic nature of most solid tumors and notoriously immunosuppressive tumor microenvironment could greatly compromise the efficacy of photodynamic immunotherapy. To address this challenge, we rationally synthesized a type I photosensitizer of TPA-DCR nanoparticles (NPs) with aggregation-enhanced reactive oxygen species generation via an oxygen-independent pathway. We demonstrated that the free radicals produced by TPA-DCR NPs could reprogram M0 and M2 macrophages into an anti-tumor state, which is not restricted by the hypoxic conditions. The activated M1 macrophages could further induce the immunogenic cell death of cancer cells by secreting pro-inflammatory cytokines and phagocytosis. In addition, in vivo anti-tumor experiments revealed that the TPA-DCR NPs could further trigger tumor immune response by re-educating tumor-associated macrophages toward M1 phenotype and promoting T cell infiltration. Overall, this work demonstrates the design of type I organic photosensitizers and mechanistic investigation of their superior anti-tumor efficacy. The results will benefit the exploration of advanced strategies to regulate the tumor microenvironment for effective photodynamic immunotherapy against hypoxic tumors.

The photosensitizer-triggered macrophage-mediated photodynamic immunotherapy is reported. The TPA-DCR NPs induce the ICD of hypoxic tumor by generating type I ROS to polarize macrophage, then promote tumor infiltration of T cells.     

Thionated organic compounds as emerging heavy-atom-free photodynamic therapy agents

This minireview focuses on recent progress in developing heavy-atom-free photosensitizers based on the thionation of nucleic acid derivatives and other biocompatible organic compounds for prospective applications in photodynamic therapy. Particular attention is given to the use of thionated nucleobase derivatives as “one-two punch” photodynamic agents. These versatile photosensitizers can act as “Trojan horses” upon metabolization into DNA and exposure to activating light. Their incorporation into cellular DNA increases their selectivity and photodynamic efficacy against highly proliferating skin cancer tumor cells, while simultaneously enabling the use of low irradiation doses both in the presence and in the absence of molecular oxygen. Also reviewed are their primary photochemical reactions, modes of action, and photosensitization mechanisms. New developments of emerging thionated organic photosensitizers absorbing visible and near-infrared radiation are highlighted. Future research directions, as well as, other prospective applications of heavy-atom-free, thionated photosensitizers are discussed.

This minireview focuses on recent progress in developing heavy-atom-free photosensitizers based on the thionation of nucleic acid derivatives and other biocompatible organic compounds for prospective applications in photodynamic therapy.     

Precisely Tuning Photothermal and Photodynamic Effects of Polymeric Nanoparticles by Controlled Copolymerization

Cancer possesses normoxic and hypoxia microenvironments with different levels of oxygen, needing different efficacies of photothermal and photodynamic therapies. It is important to precisely tune the photothermal and photodynamic effects of phototherapy nano‐agents for efficient cancer treatment. Now, a series of copolymeric nanoparticles (PPy‐Te NPs) were synthesized in situ by controlled oxidative copolymerization with different ratios of pyrrole to tellurophene by FeCl₃. The photothermal and photodynamic effects of semiconducting nano‐agents under the first near‐infrared (NIR) irradiation were precisely and systematically tuned upon simply varying the molar ratio of the pyrrole to tellurophene. The PPy‐Te NPs were used for cancer treatment in mice, exhibiting excellent biocompatibility and therapeutic effect. This work presents a simple method to tune photothermal and photodynamic therapies effect in semiconducting nano‐agents for cancer treatment.     

Enhancing the photodynamic therapy efficacy of black phosphorus nanosheets by covalently grafting fullerene C60

Few-layer black phosphorus (BP) nanosheets show potential application in biomedicine such as photodynamic therapy (PDT), and are therefore commonly used in anticancer therapy and nanomedicine due to being relatively less invasive. However, they suffer from low ambient stability and poor therapeutic efficacy. Herein, C₆₀ was covalently grafted onto the edges of BP nanosheets, and the resultant BP-C₆₀ hybrid was applied as a novel endocytosing photosensitizer, resulting in not only significantly enhanced PDT efficacy relative to that of the pristine BP nanosheets, but also drastically improved stability in a physiological environment, as confirmed by both in vitro and in vivo studies. Such improved stability was due to shielding effect of the stable hydrophobic C₆₀ molecules. The enhanced PDT efficacy is interpreted from the photoinduced electron transfer from BP to C₆₀, leading to the promoted generation of ˙OH radicals, acting as a reactive oxygen species (ROS) that is effective in killing tumor cells. Furthermore, the BP-C₆₀ hybrid exhibited low systemic toxicity in the major organs of mice. The BP-C₆₀ hybrid represents the first BP-fullerene hybrid nanomaterial fulfilling promoted ROS generation and consequently enhanced PDT efficacy.

Covalently grafting C₆₀ molecules onto black phosphorus (BP) nanosheets improves their tumor inhibition rate from 36.6% to 88.2%.     

Activatable molecular agents for cancer theranostics

Theranostics that integrates diagnosis and treatment modalities has attracted great attention due to its abilities of personalized therapy and real-time monitoring of therapeutic outcome. Such a theranostic paradigm requires agents to simultaneously possess the capabilities of targeting, imaging, and treatment. Activatable molecular agents (AMAs) are promising for cancer theranostics, as they show a higher signal-to-noise ratio (SNR), real-time detection of cancer-associated biomarkers, lower normal tissue toxicity, and a higher therapeutic effect. This perspective summarizes the recent advancements of AMAs, which include imaging-guided chemotherapy, imaging-guided photodynamic therapy, and imaging-guided photothermal therapy. The molecular design principles, theranostic mechanisms, and biomedical applications of AMAs are described, followed by a discussion of potential challenges of AMAs in cancer theranostics.

Activatable molecualr agents that intergrate diagnosis and treatment modalities have attracted great attention due to its abilities of personalized therapy and real-time monitoring of therapeutic outcome.     

A pH-responsive ultrathin Cu-based nanoplatform for specific photothermal and chemodynamic synergistic therapy

Noninvasive tumor therapy requires a new generation of bionanomaterials towards sensitive response to the unique tumor microenvironment to achieve accurate and effective treatment. Herein, we have developed a tumor therapy nanoplatform by immobilizing natural glucose oxidase (GOD) onto Cu-based layered double hydroxide (CuFe-LDH) nanosheets, which for the first time integrates acid-enhanced photothermal therapy (PTT), and pH-responsive and heat-facilitated chemodynamic therapy (CDT) simultaneously. As demonstrated by EXAFS and HRTEM, CuFe-LDH nanosheets possess a considerable number of defects caused by different acid conditions, resulting in a significantly acid-enhanced photothermal conversion efficiency (83.2% at pH 5.4 vs. 46.0% at pH 7.4). Moreover, GOD/CuFe-LDH nanosheets can convert a cascade of glucose into hydroxyl radicals (˙OH) under tumor acid conditions, which is validated by a high maximum velocity (V_max = 2.00 × 10⁻⁷ M) and low Michaelis–Menten constant (K_M = 12.01 mM). With the combination of PTT and CDT, the tumor tissue in vivo is almost eliminated with low-dose drug injection (1 mg kg⁻¹). Therefore, this novel pH-responsive Cu-based nanoplatform holds great promise in tumor-specific CDT/PTT synergistic therapy.

A pH-responsive multifunctional nanosystem was synthesized by loading glucose oxidase (GOD) onto CuFe-layered double hydroxide (LDH) nanosheets, which exhibited synchronous acid-enhanced/responsive photothermal and chemodynamic synergistic therapy.     

Tumor chemical suffocation therapy by dual respiratory inhibitions

The extraordinarily rapid growth of malignant tumors depends heavily on the glucose metabolism by the pathways of glycolysis and mitochondrial oxidative phosphorylation to generate adenosine 5′-triphosphate (ATP) for maintaining cell proliferation and tumor growth. This study reports a tumor chemical suffocation therapeutic strategy by concurrently suppressing both glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) via the co-deliveries of EDTA and rotenone into a glutathione (GSH)-overexpressed tumor microenvironment. EDTA is to block the glycolytic pathway through inhibiting the activity of glycolytic enzymes via the chelation of magnesium ion, a co-worker of glycolytic enzymes, despite the presence of Ca²⁺. Meanwhile rotenone is to inhibit the mitochondrial OXPHOS. This work provides a novel tumor suffocation strategy by the co-deliveries of glucose metabolism inhibitors, especially by de-functioning glycolytic enzymes via eliminating their co-worker magnesium.

The EDTA- and Rotenone-loaded MPER nanoparticles have been synthesized to suffocate tumor cells to death through inhibiting glycolytic process and mitochondrial oxidative phosphorylation simultaneously in vitro and in vivo.