Near‐Infrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent pH‐/H2O2‐Responsive O2‐Evolving Synergetic Cancer Therapy

Tumor hypoxia is typically presented in the central region of solid tumors, which is mainly caused by an inadequate blood flow and oxygen supply. In the conventional treatment of hypoxic human tumors, not only the oxygen‐dependent photodynamic therapy (PDT), but also antitumor drug‐based chemotherapy, is considerably limited. The use of direct oxygen delivering approach with oxygen‐dependent PDT or chemotherapy may potentiate the reactive oxygen species (ROS)‐mediated cytotoxicity of the drug toward normal tissues. Herein, a synergetic one‐for‐all mesoporous cerium oxide upconversion biophotocatalyst is developed to achieve intratumorally endogenous H₂O₂‐responsive self‐sufficiency of O₂ and near‐infrared light controlled PDT simultaneously for overcoming hypoxia cancer. Furthermore, the sufficient O₂ plays an important role in overcoming the chemotherapeutic drug‐resistant cancer caused by hypoxia, therefore inducing tumor cell apoptosis significantly.     

Multifunctional RbxWO3 Nanorods for Simultaneous Combined Chemo‐photothermal Therapy and Photoacoustic/CT Imaging

Light‐triggered drug delivery based on near‐infrared (NIR)‐mediated photothermal nanocarriers has received tremendous attention for the construction of cooperative therapeutic systems in nanomedicine. Herein, a new paradigm of light‐responsive drug carrier that doubles as a photothermal agent is reported based on the NIR light‐absorber, Rb _x WO₃ (rubidium tungsten bronze, Rb‐TB) nanorods. With doxorubicin (DOX) payload, the DOX‐loaded Rb‐TB composite (Rb‐TB‐DOX) simultaneously provides a burst‐like drug release and intense heating effect upon 808‐nm NIR light exposure. MTT assays show the photothermally enhanced antitumor activity of Rb‐TB‐DOX to the MCF‐7 cancer cells. Most remarkably, Rb‐TB‐DOX combined with NIR irradiation also shows dramatically enhanced chemotherapeutic effect to DOX‐resistant MCF‐7 cells compared with free DOX, demonstrating the enhanced efficacy of combinational chemo‐photothermal therapy for potentially overcoming drug resistance in cancer chemotherapy. Furthermore, in vivo study of combined chemo‐photothermal therapy is also conducted and realized on pancreatic (Pance‐1) tumor‐bearing nude mice. Apart from its promise for cancer therapy, the as‐prepared Rb‐TB can also be employed as a new dual‐modal contrast agent for photoacoustic tomography and (PAT) X‐ray computed tomography (CT) imaging because of its high NIR optical absorption capability and strong X‐ray attenuation ability, respectively. The results presented in the current study suggest promise of the multifunctional Rb _x WO₃ nanorods for applications in cancer theranostics.     

Dual Intratumoral Redox/Enzyme‐Responsive NO‐Releasing Nanomedicine for the Specific,High‐Efficacy,and Low‐Toxic Cancer Therapy

Chemotherapy suffers numbers of limitations including poor drug solubility, nonspecific biodistribution, and inevitable adverse effects on normal tissues. Tumor‐targeted delivery and intratumoral stimuli‐responsive release of drugs by nanomedicines are considered to be highly promising in solving these problems. Compared with traditional chemotherapeutic drugs, high concentration of nitric oxide (NO) exhibits unique anticancer effects. The development of tumor‐targeting and intratumoral microenvironment‐responsive NO‐releasing nanomedicines is highly desired. Here a novel kind of organic–inorganic composite nanomedicine (QM‐NPQ@PDHNs) is presented by encapsulating a glutathione S‐transferases π (GSTπ)‐responsive drug O²‐(2,4‐dinitro‐5‐{[2‐(β‐d ‐galactopyranosyl olean‐12‐en‐28‐oate‐3‐yl)‐oxy‐2‐oxoethyl] piperazine‐1‐yl} phenyl) 1‐(methylethanolamino)diazen‐1‐ium‐1,2‐dilate (NPQ) as NO donor and an aggregation‐induced‐emission (AIE) red fluorogen QM‐2 into the cores of the hybrid nanomicelles (PEGylated disulfide‐doped hybrid nanocarriers (PDHNs)) with glutathione (GSH)‐responsive shells. The QM‐NPQ@PDHN nanomedicine is able to respond to the intratumoral over‐expressed GSH and GSTπ, resulting in the responsive biodegradation of the protective organosilica shell and NPQ release, and subsequent NO release within the tumor, respectively, and thus normal organs remain unaffected. This work demonstrates a paradigm of dual intratumoral redox/enzyme‐responsive NO‐release nanomedicine for tumor‐specific and high‐efficacy cancer therapy.     

Co‐Delivery of Doxorubicin and siRNA with Reduction and pH Dually Sensitive Nanocarrier for Synergistic Cancer Therapy

Drug resistance is the greatest challenge in clinical cancer chemotherapy. Co‐delivery of chemotherapeutic drugs and siRNA to tumor cells is a vital means to silence drug resistant genes during the course of cancer chemotherapy for an improved chemotherapeutic effect. This study aims at effective co‐delivery of siRNA and anticancer drugs to tumor cells. A ternary block copolymer PEG‐PAsp(AED)‐PDPA consisting of pH‐sensitive poly(2‐(diisopropyl amino)ethyl methacrylate) (PDPA), reduction‐sensitive poly(N‐(2,2′‐dithiobis(ethylamine)) aspartamide) PAsp(AED), and poly(ethylene glycol) (PEG) is synthesized and assembled into a core‐shell structural micelle which encapsulated doxorubicin (DOX) in its pH‐sensitive core and the siRNA‐targeting anti‐apoptosis BCL‐2 gene (BCL‐2 siRNA) in a reduction‐sensitive interlayer. At the optimized size and zeta potential, the nanocarriers loaded with DOX and BCL‐2 siRNA may effectively accumulate in the tumor site via blood circulation. Moreover, the dual stimuli‐responsive design of micellar carriers allows microenviroment‐specific rapid release of both DOX and BCL‐2 siRNA inside acidic lysosomes with enriched reducing agent, glutathione (GSH, up to 10 mm ). Consequently, the expression of anti‐apoptotic BCL‐2 protein induced by DOX treatment is significantly down‐regulated, which results in synergistically enhanced apoptosis of human ovarian cancer SKOV‐3 cells and thus dramatically inhibited tumor growth.     

Toxic Reactive Oxygen Species Enhanced Synergistic Combination Therapy by Self‐Assembled Metal‐Phenolic Network Nanoparticles

Engineering functional nanomaterials with high therapeutic efficacy and minimum side effects has increasingly become a promising strategy for cancer treatment. Herein, a reactive oxygen species (ROS) enhanced combination chemotherapy platform is designed via a biocompatible metal‐polyphenol networks self‐assembly process by encapsulating doxorubicin (DOX) and platinum prodrugs in nanoparticles. Both DOX and platinum drugs can activate nicotinamide adenine dinucleotide phosphate oxidases, generating superoxide radicals (O₂^??). The superoxide dismutase‐like activity of polyphenols can catalyze H₂O₂ generation from O₂^??. Finally, the highly toxic HO^? free radicals are generated by a Fenton reaction. The ROS HO^? can synergize the chemotherapy by a cascade of bioreactions. Positron emission tomography imaging of ⁸⁹Zr‐labeled as‐prepared DOX@Pt prodrug Fe³⁺ nanoparticles (DPPF NPs) shows prolonged blood circulation and high tumor accumulation. Furthermore, the DPPF NPs can effectively inhibit tumor growth and reduce the side effects of anticancer drugs. This study establishes a novel ROS promoted synergistic nanomedicine platform for cancer therapy.     

A Multifunctional Cascade Bioreactor Based on Hollow‐Structured Cu2MoS4 for Synergetic Cancer Chemo‐Dynamic Therapy/Starvation Therapy/Phototherapy/Immunotherapy with Remarkably Enhanced Efficacy

The unique tumor microenvironment (TME) facilitates cancer proliferation and metastasis, and it is hard to cure cancer completely via monotherapy. Herein, a multifunctional cascade bioreactor based on hollow mesoporous Cu₂MoS₄ (CMS) loaded with glucose oxidase (GOx) is constructed for synergetic cancer therapy by chemo‐dynamic therapy (CDT)/starvation therapy/phototherapy/immunotherapy. The CMS harboring multivalent elements (Cu^1+/2+, Mo^4+/6+) exhibit Fenton‐like, glutathione (GSH) peroxidase‐like and catalase‐like activity. Once internalized into the tumor, CMS could generate ·OH for CDT via Fenton‐like reaction and deplete overexpressed GSH in TME to alleviate antioxidant capability of the tumors. Moreover, under hypoxia TME, the catalase‐like CMS could react with endogenous H₂O₂ to generate O₂ for activating the catalyzed oxidation of glucose by GOx for starvation therapy accompanied with the regeneration of H₂O₂. The regenerated H₂O₂ can devote to Fenton‐like reaction for realizing GOx‐catalysis‐enhanced CDT. Meanwhile, the CMS under 1064 nm laser irradiation shows remarkable tumor‐killing ability by phototherapy due to its excellent photothermal conversion efficiency (η = 63.3%) and cytotoxic superoxide anion (·O₂^?) generation performance. More importantly, the PEGylated CMS@GOx‐based synergistic therapy combined with checkpoint blockade therapy could elicit robust immune responses for both effectively ablating primary tumors and inhibiting cancer metastasis.     

H2S‐Scavenged and Activated Iron Oxide‐Hydroxide Nanospindles for MRI‐Guided Photothermal Therapy and Ferroptosis in Colon Cancer

Overproduced hydrogen sulfide (H₂S) is of vital importance for the progress of colon cancer and promotes cancer cellular proliferation. Devising pharmacological nanomaterials for tumor‐specific H₂S activation will be significant for precise colon cancer treatment. Herein, a biocompatible fusiform iron oxide‐hydroxide nanospindles (FeOOH NSs) nanosystem for magnetic resonance imaging (MRI), ferroptosis, and H₂S based cascade reaction‐enhanced combinational colon cancer treatment is developed. The FeOOH NSs can effectively scavenge endogenous H₂S via the reduction reaction to prohibit the growth of CT26 colon cancer. The cascade produced FeS driven by overexpressed H₂S exhibits near‐infrared‐triggered photothermal therapy capability and Fe²⁺‐mediated ferroptosis functionality. Meanwhile, the as‐prepared FeOOH NSs can light up tumor tissues as a potent MRI contrast agent. Additionally, FeOOH NSs present desirable biosafety in a murine model for up to three months and avoid any long‐term toxicity. Furthermore, it is found that these H₂S‐responsible nanotheranostics do not cause any cure effects on other cancer types, such as 4T1 breast cancer. Overall, the findings illustrate that the biocompatible FeOOH NSs can be successfully employed as a theranostic for specifically treating colon cancer, which may promote the clinical translation and development of H₂S‐responsive nanoplatforms.     

Photoconversion‐Tunable Fluorophore Vesicles for Wavelength‐Dependent Photoinduced Cancer Therapy

Photoconversion tunability of fluorophore dye is of great interest in cancer nanomedicine such as fluorescence imaging, photodynamic therapy (PDT), and photothermal therapy (PTT). Herein, this paper reports wavelength‐dependent photoconversional polymeric vesicles of boron dipyrromethene (Bodipy) fluorophore for either PDT under 660 nm irradiation or PTT under 785 nm irradiation. After being assembled within polymeric vesicles at a high drug loading, Bodipy molecules aggregate in the conformations of both J‐type and H‐type, thereby causing red‐shifted absorption into near‐infrared region, ultralow radiative transition, and ideal resistance to photobleaching. Such vesicles further possess enhanced blood circulation, preferable tumor accumulation, as well as superior cell uptake as compared to free Bodipy. In particular, the vesicles mainly generate abundant intracellular singlet oxygen for PDT treatment under 660 nm irradiation, while they primarily produce a potent hyperthermia for PTT with tumor ablation through singlet oxygen‐synergized photothermal necrosis under 785 nm irradiation. This approach provides a facile and general strategy to tune photoconversion characteristics of fluorophore dyes for wavelength‐dependent photoinduced cancer therapy.     

Copper-Enriched Prussian Blue Nanomedicine for In Situ Disulfiram Toxification and Photothermal Antitumor Amplification

In situ toxification of less toxic substance for the generation of effective anticarcinogens at the specific tumor tissue has been a novel paradigm for combating cancer. Significant efforts have been recently dedicated to turning clinical-approved drugs into anticancer agents in specific tumor microenvironment by chemical reactions. Herein, a hollow mesoporous Prussian blue (HMPB)-based therapeutic nanoplatform, denoted as DSF@PVP/Cu-HMPB, is constructed by encapsulating alcohol-abuse drug disulfiram (DSF) into the copper-enriched and polyvinylpyrrolidone (PVP)-decorated HMPB nanoparticles to achieve in situ chemical reaction-activated and hyperthermia-amplified chemotherapy of DSF. Upon tumor accumulation of DSF@PVP/Cu-HMPB, the endogenous mild acidity in tumor condition triggers the biodegradation of the HMPB nanoparticle and the concurrent co-releases of DSF and Cu²⁺, thus forming cytotoxic bis(N,N-diethyl dithiocarbamato)copper(II) complexes (CuL₂) via DSF-Cu²⁺ chelating reaction. Moreover, by the intrinsic photothermal-conversion effect of PVP/Cu-HMPBs, the anticancer effect of DSF is augmented by the hyperthermia generated upon near-infrared irradiation, thus inducing remarkable cell apoptosis in vitro and tumor elimination in vivo on both subcutaneous and orthotopic tumor-bearing models. This strategy of in situ drug transition by chemical chelation reaction and photothermal-augmentation provides a promising paradigm for designing novel cancer-therapeutic nanoplatforms.     

Monolayer Nanosheets with an Extremely High Drug Loading toward Controlled Delivery and Cancer Theranostics

2D nanomaterials have attracted considerable research interest in drug delivery systems, owing to their intriguing quantum size and surface effect. Herein, Gd³⁺‐doped monolayered‐double‐hydroxide (MLDH) nanosheets are prepared via a facile bottom‐up synthesis method, with a precisely controlled composition and uniform morphology. MLDH nanosheets as drug carrier are demonstrated in coloading of doxorubicin and indocyanine green (DOX&ICG), with an ultrahigh drug loading content (LC) of 797.36% and an encapsulation efficiency (EE) of 99.67%. This is, as far as it is known, the highest LC level at nearly 100% of EE among previously reported 2D drug delivery systems so far. Interestingly, the as‐prepared DOX&ICG/MLDH composite material shows both pH‐controlled and near‐infrared‐irradiation‐induced DOX release, which holds a promise in stimulated drug release. An in vivo dual‐mode imaging, including near‐infrared fluorescence and magnetic resonance imaging, enables a noninvasive visualization of distribution profiles at the tumor site. In addition, in vitro and in vivo therapeutic evaluations demonstrate an excellent trimode synergetic anticancer activity and superior biocompatibility of DOX&ICG/MLDH. Therefore, MLDH nanosheets provide new perspectives in the design of multifunctional nanomedicine, which shows promising applications in controlled drug delivery and cancer theranostics.     

Self-Assembled Copper-Based Nanoparticles for Glutathione Activated and Enzymatic Cascade-Enhanced Ferroptosis and Immunotherapy in Cancer Treatment

As an emerging cancer treatment strategy, ferroptosis is greatly restricted by excessive glutathione (GSH) in tumor microenvironment (TME) and low reactive oxygen species (ROS) generation efficiency. Here, this work designs self-assembled copper-alanine nanoparticles (CACG) loaded with glucose oxidase (GOx) and cinnamaldehyde (Cin) for in situ glutathione activated and enzymatic cascade-enhanced ferroptosis and immunotherapy. In response to GSH-rich and acidic TME, CACG allows to effectively co-deliver Cu²⁺, Cin, and GOx into tumors. Released Cin consumes GSH through Michael addition, accompanying with the reduction of Cu²⁺ into Cu⁺ for further GSH depletion. With the cascade of Cu⁺-catalyzed Fenton reactions and enzyme-catalyzed reactions by GOx, CACG could get rid of the restriction of insufficient hydrogen peroxide in TME, leading to a robust and constant generation of ROS. With the high efficiency of GSH depletion and ROS production, ferroptosis is significantly enhanced by CACG in vivo. Moreover, elevated oxidative stress triggers robust immune responses by promoting dendritic cells maturation and T cell infiltration. The in vivo results prove that CACG could efficiently inhibit tumor growth in 4T1 tumor-bearing mouse model without causing obvious systemic toxicity, suggesting the great potential of CACG in enhancing ferroptosis and immunotherapy for effective cancer treatment.     

A Glucose/Oxygen‐Exhausting Nanoreactor for Starvation‐ and Hypoxia‐Activated Sustainable and Cascade Chemo‐Chemodynamic Therapy

Fenton reaction‐mediated chemodynamic therapy (CDT) can kill cancer cells via the conversion of H₂O₂ to highly toxic HO?. However, problems such as insufficient H₂O₂ levels in the tumor tissue and low Fenton reaction efficiency severely limit the performance of CDT. Here, the prodrug tirapazamine (TPZ)‐loaded human serum albumin (HSA)–glucose oxidase (GOx) mixture is prepared and modified with a metal–polyphenol network composed of ferric ions (Fe³⁺) and tannic acid (TA), to obtain a self‐amplified nanoreactor termed HSA–GOx–TPZ–Fe³⁺–TA (HGTFT) for sustainable and cascade cancer therapy with exogenous H₂O₂ production and TA‐accelerated Fe³⁺/Fe²⁺ conversion. The HGTFT nanoreactor can efficiently convert oxygen into HO? for CDT, consume glucose for starvation therapy, and provide a hypoxic environment for TPZ radical‐mediated chemotherapy. Besides, it is revealed that the nanoreactor can significantly elevate the intracellular reactive oxygen species content and hypoxia level, decrease the intracellular glutathione content, and release metal ions in the tumors for metal ion interference therapy (also termed “ion‐interference therapy” or “metal ion therapy”). Further, the nanoreactor can also increase the tumor’s hypoxia level and efficiently inhibit tumor growth. It is believed that this tumor microenvironment‐regulable nanoreactor with sustainable and cascade anticancer performance and excellent biosafety represents an advance in nanomedicine.     

Emerging Nanotechnology and Advanced Materials for Cancer Radiation Therapy

Radiation therapy (RT) including external beam radiotherapy (EBRT) and internal radioisotope therapy (RIT) has been widely used for clinical cancer treatment. However, owing to the low radiation absorption of tumors, high doses of ionizing radiations are often needed during RT, leading to severe damages to normal tissues adjacent to tumors. Meanwhile, the RT efficacies are limited by different mechanisms, among which the tumor hypoxia‐associated radiation resistance is a well‐known one, as there exists hypoxia inside most solid tumors while oxygen is essential to enhance radiation‐induced DNA damages. With the development in nanotechnology, there have been great interests in using nanomedicine strategies to enhance radiation responses of tumors. Nanomaterials containing high‐Z elements to absorb radiation rays (e.g. X‐ray) can act as radio‐sensitizers to deposit radiation energy within tumors and promote treatment efficacy. Nanoscale carriers are able to deliver therapeutic radioisotopes into tumors for internal RIT, or chemotherapeutic drugs for synergistically combined chemo‐radiotherapy. As uncovered in recent studies, the tumor microenvironment could be modulated by various nanomedicine approaches to overcome hypoxia‐associated radiation resistance. Herein, the authors will summarize the applications of nanomedicine for RT cancer treatment, and pay particular attention to the latest development of ‘advanced materials' for enhanced cancer RT.     

Nanoparticle‐Enhanced Radiotherapy to Trigger Robust Cancer Immunotherapy

External radiotherapy is extensively used in clinic to destruct tumors by locally applied ionizing‐radiation beams. However, the efficacy of radiotherapy is usually limited by tumor hypoxia‐associated radiation resistance. Moreover, as a local treatment technique, radiotherapy can hardly control tumor metastases, the major cause of cancer death. Herein, core–shell nanoparticles based poly(lactic‐co‐glycolic) acid (PLGA) are fabricate, by encapsulating water‐soluble catalase (Cat), an enzyme that can decompose H₂O₂ to generate O₂, inside the inner core, and loading hydrophobic imiquimod (R837), a Toll‐like‐receptor‐7 agonist, within the PLGA shell. The formed PLGA‐R837@Cat nanoparticles can greatly enhance radiotherapy efficacy by relieving the tumor hypoxia and modulating the immune‐suppressive tumor microenvironment. The tumor‐associated antigens generated postradiotherapy‐induced immunogenic cell death in the presence of such R837‐loaded adjuvant nanoparticles will induce strong antitumor immune responses, which together with cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4) checkpoint blockade will be able to effectively inhibit tumor metastases by a strong abscopal effect. Moreover, a long term immunological memory effect to protect mice from tumor rechallenging is observed post such treatment. This work thus presents a unique nanomedicine approach as a next‐generation radiotherapy strategy to enable synergistic whole‐body therapeutic responses after local treatment, greatly promising for clinical translation.     

Synergistic Amplification of Oxidative Stress–Mediated Antitumor Activity via Liposomal Dichloroacetic Acid and MOF‐Fe2+

Cancer cells are susceptible to oxidative stress; therefore, selective elevation of intracellular reactive oxygen species (ROS) is considered as an effective antitumor treatment. Here, a liposomal formulation of dichloroacetic acid (DCA) and metal–organic framework (MOF)‐Fe²⁺ (MD@Lip) has been developed, which can efficiently stimulate ROS‐mediated cancer cell apoptosis in vitro and in vivo. MD@Lip can not only improve aqueous solubility of octahedral MOF‐Fe²⁺, but also generate an acidic microenvironment to activate a MOF‐Fe²⁺‐based Fenton reaction. Importantly, MD@Lip promotes DCA‐mediated mitochondrial aerobic oxidation to increase intracellular hydrogen peroxide (H₂O₂), which can be consequently converted to highly cytotoxic hydroxyl radicals (?OH) via MOF‐Fe²⁺, leading to amplification of cancer cell apoptosis. Particularly, MD@Lip can selectively accumulate in tumors, and efficiently inhibit tumor growth with minimal systemic adverse effects. Therefore, liposome‐based combination therapy of DCA and MOF‐Fe²⁺ provides a promising oxidative stress–associated antitumor strategy for the management of malignant tumors.     

Albumin‐Templated Manganese Dioxide Nanoparticles for Enhanced Radioisotope Therapy

Although nanoparticle‐based drug delivery systems have been widely explored for tumor‐targeted delivery of radioisotope therapy (RIT), the hypoxia zones of tumors on one hand can hardly be reached by nanoparticles with relatively large sizes due to their limited intratumoral diffusion ability, on the other hand often exhibit hypoxia‐associated resistance to radiation‐induced cell damage. To improve RIT treatment of solid tumors, herein, radionuclide ¹³¹I labeled human serum albumin (HSA)‐bound manganese dioxide nanoparticles (¹³¹I‐HSA‐MnO₂) are developed as a novel RIT nanomedicine platform that is responsive to the tumor microenvironment (TME). Such ¹³¹I‐HSA‐MnO₂ nanoparticles with suitable sizes during blood circulation show rather efficient tumor passive uptake owing to the enhanced permeability and retention effect, as well as little retention in other normal organs to minimize radiotoxicity. The acidic TME can trigger gradual degradation of MnO₂ and thus decomposition of ¹³¹I‐HSA‐MnO₂ nanoparticles into individual ¹³¹I‐HSA with sub‐10 nm sizes and greatly improves intratumoral diffusion. Furthermore, oxygen produced by MnO₂‐triggered decomposition of tumor endogenous H₂O₂ would be helpful to relieve hypoxia‐associated RIT resistant for those tumors. As the results, the ¹³¹I‐HSA‐MnO₂ nanoparticles appear to be a highly effective RIT agent showing great efficacy in tumor treatment upon systemic administration.     

Copper-Based Metal-Organic Framework Induces NO Generation for Synergistic Tumor Therapy and Antimetastasis Activity

The interaction between platelets and circulating tumor cells (CTCs) contributes to distal tumor metastasis by protecting CTCs from immunological assault and shear stress, which can be disrupted by nitric oxide (NO) through inhibiting platelet-mediated adhesion. To eradicate primitive tumors and inhibit CTC-based pulmonary metastasis, a novel biomimetic nanomedicine (mCuMNO) is designed by encapsulating Cu⁺-responsive S-nitrosoglutathione as a NO donor into a copper-based metal-organic framework (CuM). This work discovers that mCuMNO can target tumor regions and deplete local glutathione (GSH) to reduce Cu²⁺ to Cu⁺, followed by triggering NO release and hydroxyl radicals ( · OH) production, thereby interrupting platelet/CTC interplay and contributing to chemodynamic therapy. Detailed studies demonstrate that mCuMNO exhibits high efficiency and safety in tumor therapy and antimetastasis activity, sheding new light on the development of CuM-based tumor synthetic therapy.     

Realizing Cancer Precision Medicine by Integrating Systems Biology and Nanomaterial Engineering

Many clinical trials for cancer precision medicine have yielded unsatisfactory results due to challenges such as drug resistance and low efficacy. Drug resistance is often caused by the complex compensatory regulation within the biomolecular network in a cancer cell. Recently, systems biological studies have modeled and simulated such complex networks to unravel the hidden mechanisms of drug resistance and identify promising new drug targets or combinatorial or sequential treatments for overcoming resistance to anticancer drugs. However, many of the identified targets or treatments present major difficulties for drug development and clinical application. Nanocarriers represent a path forward for developing therapies with these “undruggable” targets or those that require precise combinatorial or sequential application, for which conventional drug delivery mechanisms are unsuitable. Conversely, a challenge in nanomedicine has been low efficacy due to heterogeneity of cancers in patients. This problem can also be resolved through systems biological approaches by identifying personalized targets for individual patients or promoting the drug responses. Therefore, integration of systems biology and nanomaterial engineering will enable the clinical application of cancer precision medicine to overcome both drug resistance of conventional treatments and low efficacy of nanomedicine due to patient heterogeneity.     

Hemoglobin Nanocrystals for Drugs Free,Synergistic Theranostics of Colon Tumor (Small 8/2023)

The conventional approach in cancer nanomedicine involves advanced drug nanocarriers delivering preloaded therapeutics to targeted tumor sites to maximize drug efficiency. However, both cancer drugs and nanocarriers inevitably produce side effects and systemic toxicity. Herein, hemoglobin nanocrystals (HbC) as drug-free theranostic nanoformulations with the tumor microenvironment (TME) activated diagnostic and therapeutic abilities towards colon tumors are introduced. HbC can release Fe²⁺ oxidized to Fe³⁺ in the Fenton reaction with tumor endogenous H₂O₂, concurrently with the generation of cytotoxic hydroxyl radicals (•OH) that allow for chemodynamic therapy (CDT). Furthermore, in situ-produced Fe³⁺ reacts with colon tumor-abundant H₂S, resulting in the production of Fe_1−xS, which provides magnetic resonance imaging (MRI) contrast and allows for NIR light-inducible photothermal therapy (PTT). In vitro and in vivo studies revealed that HbC produced CDT towards 4T1 tumors, and MRI-guided, synergistically enhanced combination of CDT and PTT against H₂S abundant colon tumors (CT26), with negligible toxicity towards normal tissues, enlightening HbC as highly efficient and biocompatible TME activated theranostic nanoplatform specific against colon cancer without any traditional drugs and drug carriers.