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.

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.

Enhanced Tumor-Specific Disulfiram Chemotherapy by In Situ Cu2+ Chelation-Initiated Nontoxicity-to-Toxicity Transition.

The antitumor activity of disulfiram (DSF), a traditional US Food and Drug Administration-approved drug for the treatment of "alcohol-dependence", is Cu2+-dependent, but the intrinsic anfractuous biodistribution of copper in the human body and copper toxicity induced by exogenous copper supply have severely hindered its in vivo application. Herein, we report an in situ Cu2+ chelation-enhanced DSF-based cancer chemotherapy technique, using a tumor-specific "nontoxicity-to-toxicity" transition strategy based on hollow mesoporous silica nanoparticles as the functional carrier. Cu2+-doped, DSF-loaded hollow mesoporous silica nanoparticles were constructed for the rapid release of Cu2+ ions induced by the mild acidic conditions of the tumor microenvironment. This resulted in the rapid biodegradation of the nanoparticles and accelerated DSF release once the particles were endocytosed into tumor cells. The resulting in situ chelation reaction between the coreleased Cu2+ ions and DSF generated toxic CuET products and concurrently, Fenton-like reactions between the generated Cu+ ions and the high levels of H2O2 resulted in the production of reactive oxygen species (ROS) in the acidic tumor microenvironment. Both in vitro cellular assays and in vivo tumor-xenograft experiments demonstrated the efficient Cu-enhanced and tumor-specific chemotherapeutic efficacy of DSF, with cocontributions from highly toxic CuET complexes and ROS generated within tumors. This work provides a conceptual advancement of nanoparticle-enabled "nontoxicity-to-toxicity" transformation in tumors, to achieving high chemotherapeutic efficacy and biosafety.

Magnesium-Engineered Silica Framework for pH-Accelerated Biodegradation and DNAzyme-Triggered Chemotherapy.

Inorganic nanocarriers have shown their high performance in disease theranostics in preclinical animal models and further great prospects for clinical translation. However, their dissatisfactory biodegradability and pre-drug leakage with nonspecificity to lesion sites significantly hinders the possible clinical translation. To solve these two critical issues, a framework-engineering strategy is introduced to simultaneously achieve enhanced biodegradability and controllable drug releasing, based on the mostly explored mesoporous silica-based nanosystems. The framework of mesoporous silica is engineered by direct Mg doping via a generic dissolution and regrowth approach, and it can transform into the easy biodegradation of magnesium silicate nanocarriers with simultaneous on-demand drug release. Such magnesium silicate nanocarriers can respond to the mild acidic environment of tumor tissue, causing the fast breaking up and biodegradation of the silica framework. More interesting, the released Mg2+ can further activate Mg2+ -dependent DNAzyme on the surface of hollow mesoporous magnesium silicate nanoparticles (HMMSNs) to cleave the RNA-based gatekeeper, which further accelerates the release of loaded anticancer drugs. Therefore, enhanced anticancer efficiency of chemotherapeutic drugs assisted by the biodegradable intelligent HMMSNs is achieved. The high biocompatibility of nanocarriers and biodegradation products is demonstrated and can be easily excreted via feces and urine guaranteeing their further clinical translation.

Two-Dimensional Ultrathin MXene Ceramic Nanosheets for Photothermal Conversion.

Ceramic biomaterials have been investigated for several decades, but their potential biomedical applications in cancer therapy have been paid much less attentions, mainly due to their lack of related material functionality for combating the cancer. In this work, we report, for the first time, that MAX ceramic biomaterials exhibit the unique functionality for the photothermal ablation of cancer upon being exfoliated into ultrathin nanosheets within atomic thickness (MXene). As a paradigm, biocompatible Ti3C2 nanosheets (MXenes) were successfully synthesized based on a two-step exfoliation strategy of MAX phase Ti3AlC2 by the combined HF etching and TPAOH intercalation. Especially, the high photothermal-conversion efficiency and in vitro/in vivo photothermal ablation of tumor of Ti3C2 nanosheets (MXenes) were revealed and demonstrated, not only in the intravenous administration of soybean phospholipid modified Ti3C2 nanosheets but also in the localized intratumoral implantation of a phase-changeable PLGA/Ti3C2 organic-inorganic hybrid. This work promises the great potential of Ti3C2 nanosheets (MXenes) as a novel ceramic photothermal agent used for cancer therapy and may arouse much interest in exploring MXene-based ceramic biomaterials to benefit the biomedical applications.

Metalloporphyrin-Encapsulated Biodegradable Nanosystems for Highly Efficient Magnetic Resonance Imaging-Guided Sonodynamic Cancer Therapy.

Traditional photodynamic therapy (PDT) suffers from the critical issues of low tissue-penetrating depth of light and potential phototoxicity, which are expected to be solved by developing new dynamic therapy-based therapeutic modalities such as sonodynamic therapy (SDT). In this work, we report on the design/fabrication of a high-performance multifunctional nanoparticulate sonosensitizer for efficient in vivo magnetic resonance imaging (MRI)-guided SDT against cancer. The developed approach takes the structural and compositional features of mesoporous organosilica-based nanosystems for the fabrication of sonosensitizers with intriguing theranostic performance. The well-defined mesoporosity facilitates the high loading of organic sonosensitizers (protoporphyrin, PpIX) and further chelating of paramagnetic transitional metal Mn ions based on metalloporphyrin chemistry (MnPpIX). The mesoporous structure of large surface area also maximizes the accessibility of water molecules to the encapsulated paramagnetic Mn ions, endowing the composite sonosensitizers with markedly high MRI performance (r1 = 9.43 mM-1 s-2) for SDT guidance and monitoring. Importantly, the developed multifunctional sonosensitizers (HMONs-MnPpIX-PEG) with controllable biodegradation behavior and high biocompatibility show distinctively high SDT efficiency for inducing the cancer-cell death in vitro and suppressing the tumor growth in vivo. This report provides a paradigm that nanotechnology-enhanced SDT based on elaborately designed high-performance multifunctional sonosensitizers will pave a new way for efficient cancer treatment by fully taking the advantages (noninvasiveness, convenience, cost-effectiveness, etc.) of ultrasound therapy and quickly developing nanomedicine.

"Manganese Extraction" Strategy Enables Tumor-Sensitive Biodegradability and Theranostics of Nanoparticles.

Biodegradability of inorganic nanoparticles is one of the most critical issues in their further clinical translations. In this work, a novel "metal ion-doping" approach has been developed to endow inorganic mesoporous silica-based nanoparticles with tumor-sensitive biodegradation and theranostic functions, simply by topological transformation of mesoporous silica to metal-doped composite nanoformulations. "Manganese extraction" sensitive to tumor microenvironment was enabled in manganese-doped hollow mesoporous silica nanoparticles (designated as Mn-HMSNs) to fast promote the disintegration and biodegradation of Mn-HMSNs, further accelerating the breakage of Si-O-Si bonds within the framework. The fast biodegradation of Mn-HMSNs sensitive to mild acidic and reducing microenvironment of tumor resulted in much accelerated anticancer drug releasing and enhanced T1-weighted magnetic resonance imaging of tumor. A high tumor-inhibition effect was simultaneously achieved by anticancer drug delivery mediated by PEGylated Mn-HMSNs, and the high biocompatibility of composite nanosystems was systematically demonstrated in vivo. This is the first demonstration of biodegradable inorganic mesoporous nanosystems with specific biodegradation behavior sensitive to tumor microenvironment, which also provides a feasible approach to realize the on-demand biodegradation of inorganic nanomaterials simply by "metal ion-doping" strategy, paving the way to solve the critical low-biodegradation issue of inorganic drug carriers.

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.

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 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.

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 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.

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.

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.

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.

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.

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.