A dual-targeting therapeutic nanobubble for imaging-guided atherosclerosis treatment.

Atherosclerosis is a cardiovascular disease that seriously endangers human health. Low shear stress (LSS) is recognized as a vital factor in causing chronic inflammatory and further inducing the occurrence and development of atherosclerosis. Targeting imaging and treatment are of substantial significance for the diagnosis and therapy of atherosclerosis. On this ground, a kind of ultrasound (US) imaging-guided therapeutic polymer nanobubbles (NBs) with dual targeting of magnetism and antibody was rationally designed and constructed for the efficiently treating LSS-mediated atherosclerosis. Under the combined targeting effect of an external magnetic field and antibodies, the drug-loaded therapeutic NBs can be effectively accumulated in the inflammatory area caused by LSS. Upon US irradiation, the NBs can be selectively disrupted, leading to the rapid release of the loaded drugs at the targeted site. Notably, the US irradiation generates a cavitation effect that induces repairable micro gaps in nearby cells, thereby enhancing the uptake of released drugs and further improving the therapeutic effect. The prominent US imaging, efficient anti-inflammatory effect and treatment outcome of LSS-mediated atherosclerosis had been verified in vivo on a surgically constructed LSS-atherosclerosis animal model. This work showcased the potential of the designed NBs with multifunctionality for in vivo imaging, dual-targeting, and drug delivery in the treatment of atherosclerosis.

Engineering Self-Assembled Nanomedicines Composed of Clinically Approved Medicines for Enhanced Tumor Nanotherapy.

The traditional nanocarriers are typically constructed to deliver anticancer agents for improving drug bioavailability and enhancing chemotherapeutic efficacy, but this strategy suffers from the critical issue of nanocarrier biosafety that hinders further clinical translation. In this work, a unique nanomedicine (PTX@ICG) has been rationally constructed by combining two clinically approved agents, i.e., paclitaxel (PTX) and indocyanine green (ICG), by a facile ultrasound-assisted self-assembly methodology. The formation of the nanostructure can effectively increase the enrichment of PTX and ICG molecules in the tumor site, and improve the utilization factor of hydrophobic PTX. Moreover, since the molecule interaction in PTX@ICG is mainly Van der Waals forces, the self-assembled structure can be spontaneously dissociated under laser irradiation and release PTX in situ to achieve safe tumor-targeted chemotherapy. Simultaneously, the released ICG can act as photothermic agents for photothermal therapy (PTT), thus combining chemotherapy and PTT to obtain an enhanced tumor nanotherapy via facile self-assembly. The synergistic chemo/photothermal tumor nanotherapy achieved the efficient tumor cell-killing effect and tumor-ablation ability, as systematically demonstrated both in vitro and in vivo. This work provides a distinct paradigm of the self-assembled nanomedicine design for effectively improving the drug bioavailability to achieve high antitumor efficacy.

Nanosonosensitizers-engineered injectable thermogel for augmented chemo-sonodynamic therapy of melanoma and infected wound healing.

Easy recurrence and bacteria infected-wound healing after surgery excision pose severe challenges to clinical melanoma therapy. Herein, an injectable CuO2 nanodots-engineered thermosensitive chitosan hydrogel (CuO2-BSO@Gel) for enhanced melanoma chemo-sonodynamic therapy and improved infected wound healing was rationally constructed by facilely integrating the CuO2 nanodots and L-Buthionine-(S, R)-sulfoximine (BSO) with thermoresponsive hydrogel. Favored by the Fenton catalytic activity of Cu2+, the CuO2 nanodots can achieve enhanced chemodynamic therapy (CDT) by self-supplying H2O2 under acidic tumor microenvironment. Simultaneously, the CuO2 nanodots with a narrow bandgap (2.29 â€‹eV) were proven to be the efficient sonosensitizers, and the corresponding quantum yield of singlet oxygen (1O2) could be boosted by the O2 generation during Fenton-like reactions. Additionally, combining with the glutathione (GSH) depletion of loaded BSO, intracellular oxidative stress induced by SDT and CDT was further amplified, leading to the specific ferroptosis. Importantly, this multifunctional hydrogel significantly promoted the proliferation of normal skin cells and accelerated the bacteria-infected wound healing by the effective chemo-sonodynamic antibacterial activity and the enhanced angiogenesis. Thus, the engineered thermogel features the distinct chemo-sonodynamic performance, desirable biocompatibility and bioactivity, providing a competitive strategy for eradicating melanoma and infected wound healing.

Engineering ROS-scavenging Prussian blue nanozymes for efficient atherosclerosis nanotherapy.

Atherosclerosis (AS), characterized by a chronic inflammatory disease, is a top cause of morbidity and disability worldwide. During the pathogenesis of AS, the leading process of inflammation highly involves a secondary event of oxidative stress, but limited antioxidants are currently available clinically due to their nonspecific effects, poor biosafety, and rapid in vivo elimination and urinary excretion as well as short retention time within plaque lesions. In this work, Prussian blue nanozymes with a strong reactive oxygen species (ROS)-scavenging ability were rationally engineered for efficient AS nanotherapy. Specifically, the obtained nanozymes with high photothermal performance could behave as potent photoacoustic imaging agents for plaque detection. In addition, these nanozymes featuring multienzyme activities could reduce the cellular ROS level, exert cytoprotective effects against ROS-mediated macrophages apoptosis, and inhibit foam cell formation, significantly boycotting AS development. The underlying mechanism was further verified by transcriptome sequencing at the cellular level and a series of immunohistochemical staining of aortic sinus sections in apoE-/- mice. Finally, the high biocompatibility and biosafety of the engineered Prussian blue nanozymes further guarantee their clinical translation potential for AS management.

Ultrasound-enhanced cascade chemodynamic tumor nanotherapy with lactic acid-enabled hydrogen peroxide self-production.

Chemodynamic therapy (CDT) is an effective therapeutic modality for cancer treatment with the action of a catalytic Fenton-like chemoreactive process. To furnish sufficient hydrogen peroxide (H2O2) for CDT, catalysts similar to superoxide dismutase are designed to be in cooperation with nanoplatforms. In this work, we rationally integrate lactate oxidase (LOD) with ultrasmall superparamagnetic iron oxide nanoparticles (USPION) to achieve high efficiency of the cascade Fenton reaction for efficient tumor therapy. During the sequential reaction, LOD converts lactic acid into H2O2 and pyruvate (PA) in situ, and then USPION with peroxidase-like activity generates large amounts of toxic hydroxyl radicals (˙OH) under the action of H2O2. Moreover, the reaction effectively utilizes the excess lactic acid of the tumor microenvironment (TME) as a new target of cancer treatment. To further achieve high-performance tumor treatment, ultrasound has been introduced for augmenting this specific chemoreactive tumor therapy, which can affect cancer cells mainly through sonoporation, cavitation, and thermal effect. With the effects of ultrasound irradiation, this work has constructed an efficient oncology treatment system for tumors. Moreover, the presence of USPION is highly desirable for contrast-enhanced T1-weighted MRI for monitoring the therapeutic process of cancer in real time.

Engineering Fe/Mn-doped zinc oxide nanosonosensitizers for ultrasound-activated and multiple ferroptosis-augmented nanodynamic tumor suppression.

As an effective tumor-therapeutic modality, ultrasound-triggered sonodynamic therapy (SDT) has been extensively explored to induce cancer cell death by activating sonosensitizers to generate reactive oxygen species (ROS). However, the traditional inorganic semiconductor-based sonosensitizers still suffer from inefficient ROS production because of the low separation efficiency of electrons and holes (e-/h+) and their fast recombination. Herein, the iron (Fe) and manganese (Mn) co-doped zinc oxide nanosonosensitizers have been rationally designed and engineered for augmenting the SDT efficiency against tumor by inducing both multiple ferroptosis and apoptosis of tumor cells. The Fe/Mn component was co-doped into the nannostructure of ZnO nanosonosensitizers, which not only catalyzed the Fenton reaction in the hydrogen peroxide-overexpressed tumor microenvironment to produce ROS, but also depleted intracellular glutathione to suppress the consumption of ROS. The doping nanostructure in the engineered nanosonosensitizers substantially augmented the SDT efficacy of ZnO nanosonosensitizers by promoting the separation and hindering the recombination of e-/h+ under ultrasound activation. The multiple ferroptosis and apoptosis in the enhanced SDT effect of Fe/Mn co-doped ZnO nanosonosensitizers were solidly demonstrated both in vitro and in vivo on tumor-bearing mice in accompany with the detailed mechanism assessment by RNA sequenching. This work provides a distinct strategy to augment the nanomedicine-enabled SDT efficency by engineering the inorganic semiconductor-based nanosonosensitizers with transitional metal doping and inducing multiple cell-death pathways including ferroptosis.

Engineering 2D Silicene-Based Mesoporous Nanomedicine for In Vivo Near-Infrared-Triggered Analgesia.

The utilization of local anesthetics for postoperative analgesia represents an effective approach, but generally suffers from short half-lives and brachychronic local neurotoxicity. A desirable anesthetic with controllable and sustainable drug-releasing performance for adequate analgesia effect is highly required. In this work, the core/shell-structured two-dimenional (2D) silicene nanosheets coated with mesoporous silica layer (abbreviated as Silicene@MSNs) have been rationally constructed as localized drug-delivery system in sciatic nerve block to achieve on-demand release of loaded ropivacaine (RP) in mesoporous silica layer for local analgesia. Based on the specific photothermal performance of 2D silicene core, this local anesthesia system can be triggered by near-infrared laser to release the loaded RP, resulting in on-demand and long-lasting regional anesthesia. The analgesia effect is assessed by pain behavior tests, which demonstrates that the RP-loaded Silicene@MSNs core/shell nanosystem behaves almost five times longer analgesia effect than free RP. Furthermore, the activation of pain-related neurons in nerve conduction pathways is tested to explore the underlying analgesia mechanism, revealing that the designed nanosystem can improve the pain threshold, reduce the activation of neurons in dorsal root ganglion and excitability in spinal substantia gelatinosa neurons. This designed anesthetic nanomedicine provides a facile but effective methodology for long-lasting regional anesthesia.

Oxygen-evolving photosynthetic cyanobacteria for 2D bismuthene radiosensitizer-enhanced cancer radiotherapy.

The local hypoxic tumor environment substantially hampers the therapeutic efficiency of radiotherapy, which typically requires the large X-ray doses for tumor treatment but induces the serious side effects. Herein, a biomimetic radiosensitized platform based on a natural in-situ oxygen-evolving photosynthetic cyanobacteria combined with two-dimensional (2D) bismuthene with high atomic-number (Z) components, is designed and engineered to effectively modulate the radiotherapy-resistant hypoxic tumor environment and achieve sufficient radiation energy deposition into tumor. Upon the exogenous sequential irradiation of 660 nm laser and X-ray beam, continuous photosynthetic oxygen evolution by the cyanobacteria and considerable generation of reactive oxygen species by the 2D bismuthene radiosensitizer substantially augmented the therapeutic efficacy of radiotherapy and suppressed the in vivo tumor growth, as demonstrated on both LLC-lung tumor xenograft-bearing C57/B6 mice model and 4T1-breast tumor xenograft-bearing Balb/c mice model, further demonstrating the photosynthetic hypoxia-alleviation capability and radiosensitization performance of the engineered biomimetic radiosensitized platform. This work exemplifies a distinct paradigm on the construction of microorganism-enabled tumor-microenvironment modulation and nanoradiosensitizer-augmented radiotherapy for efficient tumor treatment.

Redox chemistry-enabled stepwise surface dual nanoparticle engineering of 2D MXenes for tumor-sensitive T1 and T2 MRI-guided photonic breast-cancer hyperthermia in the NIR-II biowindow.

With the fast advent of two-dimensional (2D) MXenes, several therapeutic paradigms based on 2D MXenes flourish, but a generic strategy for MXene functionalization to achieve theranostic functionalities and desirable performance is still lacking. In this work, we report a facile and efficient stepwise surface-functionalization strategy to achieve distinct tumor microenvironment (TME)-responsive T1 and T2 magnetic resonance (MR) imaging-guided photothermal breast-cancer hyperthermia in the second near-infrared (NIR-II) biowindow. This approach is based on the stepwise growth of superparamagnetic Fe3O4 and paramagnetic MnOx nanocomponents onto the large surface of ultrathin 2D niobium carbide (Nb2C) MXene nanosheets (Fe3O4/MnOx-Nb2C) by making full use of the redox status/chemistry of the 2D MXene surface. Such a surface-nanoparticle engineering strategy endows Fe3O4/MnOx-Nb2C composite nanosheets with a series of properties that include high photothermal-conversion efficiency in the NIR-II biowindow (1064 nm, η 30.9%) for effective photothermal tumor eradication without further reoccurrence. It also allows TME-responsive T1- and T2-weighted MR imaging and high biocompatibility for guaranteeing further potential clinical transformation. This work not only makes the efficient diagnostic T1- and T2-weighted MR imaging-guided photonic hyperthermia of breast cancer possible, but also broadens the biomedical applications of MXene-based nanoplatforms by developing novel surface-engineering strategies to construct 2D Nb2C MXene-based composite multifunctional nanoplatforms.

Multifunctional Composite Nanosystems for Precise/Enhanced Sonodynamic Oxidative Tumor Treatment.

Ultrasound-activated therapies have been regarded as the efficient strategy for tumor treatment, among which sonosensitizer-enabled sonodynamic oxidative tumor therapy features intrinsic advantages as compared to other exogenous trigger-activated dynamic therapies. Nanomedicine-based nanosonosensitizer design has been extensively explored for improving the therapeutic efficacy of sonodynamic therapy (SDT) of tumor. This review focuses on solving two specific issues, i.e., precise and enhanced sonodynamic oxidative tumor treatment, by rationally designing and engineering multifunctional composite nanosonosensitizers. This multifunctional design can augment the therapeutic efficacy of SDT against tumor by either improving the production of reactive oxygen species or inducing the synergistic effect of SDT-based combinatorial therapies. Especially, this multifunctional design is also capable of endowing the nanosonosensitizer with bioimaging functionality, which can effectively guide and monitor the therapeutic procedure of the introduced sonodynamic oxidative tumor treatment. The design principles, underlying material chemistry for constructing multifunctional composite nanosonosensitizers, intrinsic synergistic mechanism, and bioimaging guided/monitored precise SDT are summarized and discussed in detail with the most representative paradigms. Finally, the existing critical issues, available challenges, and potential future developments of this research area are also discussed for promoting the further clinical translations of these multifunctional composite nanosonosensitizers in SDT-based tumor treatment.

Co-delivery of nanoparticle and molecular drug by hollow mesoporous organosilica for tumor-activated and photothermal-augmented chemotherapy of breast cancer.

BACKGROUND: In comparison with traditional therapeutics, it is highly preferable to develop a combinatorial therapeutic modality for nanomedicine and photothermal hyperthermia to achieve safe, efficient, and localized delivery of chemotherapeutic drugs into tumor tissues and exert tumor-activated nanotherapy. Biocompatible organic-inorganic hybrid hollow mesoporous organosilica nanoparticles (HMONs) have shown high performance in molecular imaging and drug delivery as compared to other inorganic nanosystems. Disulfiram (DSF), an alcohol-abuse drug, can act as a chemotherapeutic agent according to its recently reported effectiveness for cancer chemotherapy, whose activity strongly depends on copper ions. RESULTS: In this work, a therapeutic construction with high biosafety and efficiency was proposed and developed for synergistic tumor-activated and photothermal-augmented chemotherapy in breast tumor eradication both in vitro and in vivo. The proposed strategy is based on the employment of HMONs to integrate ultrasmall photothermal CuS particles onto the surface of the organosilica and the molecular drug DSF inside the mesopores and hollow interior. The ultrasmall CuS acted as both photothermal agent under near-infrared (NIR) irradiation for photonic tumor hyperthermia and Cu2+ self-supplier in an acidic tumor microenvironment to activate the nontoxic DSF drug into a highly toxic diethyldithiocarbamate (DTC)-copper complex for enhanced DSF chemotherapy, which effectively achieved a remarkable synergistic in-situ anticancer outcome with minimal side effects. CONCLUSION: This work provides a representative paradigm on the engineering of combinatorial therapeutic nanomedicine with both exogenous response for photonic tumor ablation and endogenous tumor microenvironment-responsive in-situ toxicity activation of a molecular drug (DSF) for augmented tumor chemotherapy.

Ultrathin 2D Inorganic Ancient Pigment Decorated 3D-Printing Scaffold Enables Photonic Hyperthermia of Osteosarcoma in NIR-II Biowindow and Concurrently Augments Bone Regeneration.

Osteosarcoma (OS) is the primary malignant bone tumor. Despite therapeutic strategies including surgery, chemotherapy, and radiotherapy have been introduced into the war of fighting OS, the 5-year survival rate for patients still remains unchangeable for decades. Besides, the critical bone defects after surgery, drug-resistance and side effects also attenuate the therapeutic effects and predict poor prognosis. Recently, photothermal therapy (PTT) has attracted extensive attention featuring minimal invasiveness and high spatial-temporal precision characteristics. Herein, an ultrathin 2D inorganic ancient pigment Egyptian blue decorated 3D-printing scaffold (CaPCu) with profound PTT efficacy at the second near-infrared (NIR-II) biowindow against OS and enhanced osteogenesis performance is successfully constructed. Importantly, this work uncovers the underlying biological mechanisms that genes associated with cell death, proliferation, and bone development are regulated by CaPCu-scaffold-based therapy. This work not only elucidates the fascinating clinical translation prospects of CaPCu-scaffold-based PTT against OS in NIR-II biowindow, but also demonstrates the potential mechanisms and offers a novel strategy to develop the next-generation, multifunctional tissue-engineering biomaterials.

Mesoporous silica nanoparticles inflame tumors to overcome anti-PD-1 resistance through TLR4-NFκB axis.

BACKGROUND: The clinical benefits of antiprogrammed cell death protein 1 (PD-1) therapy are compromised by resistance in immunologically cold tumors. Convergence of immunotherapy and bioengineering is potential to overcome the resistance. Mesoporous silica nanoparticles (MSNs) are considered the most promising inorganic biological nanomaterials for clinical transformation, however, the fundamental influence of MSNs on immunotherapy is unclear. In this study, we aimed to investigate the role of MSNs in tumor resensitization and explore the feasibility of MSNs combined with anti-PD-1 in cancer therapy. METHODS: Intrinsic and acquired resistant tumors, as well as spontaneous and secondary tumor recurrence models, were used to evaluate the influence of MSNs and the synergistical effect with anti-PD-1 therapy. The roles of CD8+ cytotoxic T-lymphocytes (CTLs) and macrophages were assessed in Rag-1-/- mice, ovalbumin/OT-1 TCR transgenic T-cell system, and other blocking mice models. Mechanistic studies were processed by transcriptomics analysis and conducted in primary cells, in vitro coculture systems, and Toll-like receptor 4 (TLR4) knockout mice. RESULTS: Both granular and rod-shaped MSNs efficiently overcame tumor resistance with dependence on diameter and aspect ratio. Only once injection of MSNs in prior to anti-PD-1 markedly improved the treatment efficacy, protective immunity, and prognosis. MSNs per se boosted infiltration of CTLs as the early event (days 2-3); and synergistically with anti-PD-1 therapy, MSNs rapidly established a T cell-inflamed microenvironment with abundant high-activated (interferon-γ/tumor necrosis factor-α/Perforin/GranzymeB) and low-exhausted (PD-1/lymphocyte-activation gene 3 (LAG-3)/T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)) CTLs. Chemokines Ccl5/Cxcl9/Cxcl10, which were produced predominantly by macrophages, promoted MSNs-induced CTLs infiltration. MSNs led to high Ccl5/Cxcl9/Cxcl10 production in vitro and in mice through regulating TLR4-NFκB axis. Blocking TLR4-NFκB axis in macrophages or CTLs infiltration abrogated MSNs-induced resensitization to anti-PD-1 therapy. CONCLUSIONS: MSNs efficiently and rapidly inflame immunologically cold tumors and resensitize them to anti-PD-1 therapy through TLR4-NFκB-Ccl5/Cxcl9/Cxcl10 axis. MSNs-based theranostic agents can serve as sensitizers for patients with resistant tumors to improve immunotherapy.

Autophagy blockade synergistically enhances nanosonosensitizer-enabled sonodynamic cancer nanotherapeutics.

Ultrasound-triggered sonodynamic therapy (SDT) represents an emerging therapeutic modality for cancer treatment based on its specific feature of noninvasiveness, high tissue-penetrating depth and desirable therapeutic efficacy, but the SDT-induced pro-survival cancer-cell autophagy would significantly lower the SDT efficacy for cancer treatment. Here we propose an "all-in-one" combined tumor-therapeutic strategy by integrating nanosonosensitizers-augmented noninvasive SDT with autophagy inhibition based on the rationally constructed nanoliposomes that co-encapsulates clinically approved sonosensitizers protoporphyrin IX (PpIX) and early-phase autophagy-blocking agent 3-methyladenine (3-MA). It has been systematically demonstrated that nanosonosensitizers-augmented SDT induced cytoprotective pro-survival autophagy through activation of MAPK signaling pathway and inhibition of AMPK signaling pathway, and this could be efficaciously inhibited by 3-MA in early-phase autophagy, which significantly decreased the cell resistance to intracellular oxidative stress and complied a remarkable synergistic effect on SDT medicated cancer-cell apoptosis both in vitro at cellular level and in vivo on tumor-bearing animal model. Therefore, our results provide a proof-of-concept combinatorial tumor therapeutics based on nanosonosensitizers for the treatment of ROS-resistant cancer by autophagy inhibition-augmented SDT.

Emerging Nanomedicine-Enabled/Enhanced Nanodynamic Therapies beyond Traditional Photodynamics.

The rapid knowledge growth of nanomedicine and nanobiotechnology enables and promotes the emergence of distinctive disease-specific therapeutic modalities, among which nanomedicine-enabled/augmented nanodynamic therapy (NDT), as triggered by either exogenous or endogenous activators on nanosensitizers, can generate reactive radicals for accomplishing efficient disease nanotherapies with mitigated side effects and endowed disease specificity. As one of the most representative modalities of NDT, traditional light-activated photodynamics suffers from the critical and unsurmountable issues of the low tissue-penetration depth of light and the phototoxicity of the photosensitizers. To overcome these obstacles, versatile nanomedicine-enabled/augmented NDTs have been explored for satisfying varied biomedical applications, which strongly depend on the physicochemical properties of the involved nanomedicines and nanosensitizers. These distinctive NDTs refer to sonodynamic therapy (SDT), thermodynamic therapy (TDT), electrodynamic therapy (EDT), piezoelectric dynamic therapy (PZDT), pyroelectric dynamic therapy (PEDT), radiodynamic therapy (RDT), and chemodynamic therapy (CDT). Herein, the critical roles, functions, and biological effects of nanomedicine (e.g., sonosensitizing, photothermal-converting, electronic, piezoelectric, pyroelectric, radiation-sensitizing, and catalytic properties) for enabling the therapeutic procedure of NDTs, are highlighted and discussed, along with the underlying therapeutic principle and optimization strategy for augmenting disease-therapeutic efficacy and biosafety. The present challenges and critical issues on the clinical translations of NDTs are also discussed and clarified.

Self-assembled organic nanomedicine enables ultrastable photo-to-heat converting theranostics in the second near-infrared biowindow.

Development of organic theranostic agents that are active in the second near-infrared (NIR-II, 1000-1700 nm) biowindow is of vital significance for treating deep-seated tumors. However, studies on organic NIR-II absorbing agents for photo-to-heat energy-converting theranostics are still rare simply because of tedious synthetic routes to construct extended π systems in the NIR-II region. Herein, we design a convenient strategy to engineer highly stable organic NIR-II absorbing theranostic nanoparticles (Nano-BFF) for effective phototheranostic applications via co-assembling first NIR (NIR-I, 650-1000 nm) absorbing boron difluoride formazanate (BFF) dye with a biocompatible polymer, endowing the Nano-BFF with remarkable theranostic performance in the NIR-II region. In vitro and in vivo investigations validate that Nano-BFF can serve as an efficient theranostic agent to achieve photoacoustic imaging guided deep-tissue photonic hyperthermia in the NIR-II biowindow, achieving dramatic inhibition toward orthotopic hepatocellular carcinoma. This work thus provides an insight into the exploration of versatile organic NIR-II absorbing nanoparticles toward future practical applications.

Nanomedicine enables autophagy-enhanced cancer-cell ferroptosis.

Ferroptosis and autophagy, playing significant roles in tumor treatment, are two typical forms of the programmed cell death. However, the rational combination of ferroptosis and autophagy for synergistic tumor therapy is still highly challenging. Herein, we report on an intriguing nanomedicine strategy for achieving autophagy-enhanced ferroptosis on efficiently combating cancer, which was based on the construction of trehalose-loaded mSiO2@MnOx-mPEG (TreMMM) nanoparticles with satisfactory biocompatibility. The nanoparticles are endowed with high glutathione (GSH) consumption efficiency, thereby inducing cancer-cell ferroptosis via inactivating glutathione peroxidases 4 (GPX4). Subsequently, the TreMMM degradation due to the GSH depletion and pH sensitivity contributed to the trehalose release for inducing autophagy, promoting/enhancing ferroptosis by NCOA4-mediated degradation of ferritin. A substantial in vitro and in vivo antitumor effect was achieved by such an intriguing autophagy-enhanced ferroptosis. Therefore, the rational combination of GSH-consumption-induced ferroptosis and trehalose-induced autophagy by nanomedicine design provides an alternative but effective strategy for tumor treatment.

Energy-converting biomaterials for cancer therapy: Category, efficiency, and biosafety.

Energy-converting biomaterials (ECBs)-mediated cancer-therapeutic modalities have been extensively explored, which have achieved remarkable benefits to overwhelm the obstacles of traditional cancer-treatment modalities. Energy-driven cancer-therapeutic modalities feature their distinctive merits, including noninvasiveness, low mammalian toxicity, adequate therapeutic outcome, and optimistical synergistic therapeutics. In this advanced review, the prevailing mainstream ECBs can be divided into two sections: Reactive oxygen species (ROS)-associated energy-converting biomaterials (ROS-ECBs) and hyperthermia-related energy-converting biomaterials (H-ECBs). On the one hand, ROS-ECBs can transfer exogenous or endogenous energy (such as light, radiation, ultrasound, or chemical) to generate and release highly toxic ROS for inducing tumor cell apoptosis/necrosis, including photo-driven ROS-ECBs for photodynamic therapy, radiation-driven ROS-ECBs for radiotherapy, ultrasound-driven ROS-ECBs for sonodynamic therapy, and chemical-driven ROS-ECBs for chemodynamic therapy. On the other hand, H-ECBs could translate the external energy (such as light and magnetic) into heat for killing tumor cells, including photo-converted H-ECBs for photothermal therapy and magnetic-converted H-ECBs for magnetic hyperthermia therapy. Additionally, the biosafety issues of ECBs are expounded preliminarily, guaranteeing the ever-stringent requirements of clinical translation. Finally, we discussed the prospects and facing challenges for constructing the new-generation ECBs for establishing intriguing energy-driven cancer-therapeutic modalities. This article is categorized under: Nanotechnology Approaches to Biology >Nanoscale Systems in Biology.

The Coppery Age: Copper (Cu)-Involved Nanotheranostics.

As an essential trace element in the human body, transitional metal copper (Cu) ions are the bioactive components within the body featuring dedicated biological effects such as promoting angiogenesis and influencing lipid/glucose metabolism. The recent substantial advances of nanotechnology and nanomedicine promote the emerging of distinctive Cu-involved biomaterial nanoplatforms with intriguing theranostic performances in biomedicine, which are originated from the biological effects of Cu species and the physiochemical attributes of Cu-composed nanoparticles. Based on the very-recent significant progresses of Cu-involved nanotheranostics, this work highlights and discusses the principles, progresses, and prospects on the elaborate design and rational construction of Cu-composed functional nanoplatforms for a diverse array of biomedical applications, including photonic nanomedicine, catalytic nanotherapeutics, antibacteria, accelerated tissue regeneration, and bioimaging. The engineering of Cu-based nanocomposites for synergistic nanotherapeutics is also exemplified, followed by revealing their intrinsic biological effects and biosafety for revolutionizing their clinical translation. Finally, the underlying critical concerns, unresolved hurdles, and future prospects on their clinical uses are analyzed and an outlook is provided. By entering the "Copper Age," these Cu-involved nanotherapeutic modalities are expected to find more broad biomedical applications in preclinical and clinical phases, despite the current research and developments still being in infancy.