Ketogenic diet reshapes cancer metabolism through lysine ß-hydroxybutyrylation.

Lysine ß-hydroxybutyrylation (Kbhb) is a post-translational modification induced by the ketogenic diet (KD), a diet showing therapeutic effects on multiple human diseases. Little is known how cellular processes are regulated by Kbhb. Here we show that protein Kbhb is strongly affected by the KD through a multi-omics analysis of mouse livers. Using a small training dataset with known functions, we developed a bioinformatics method for the prediction of functionally important lysine modification sites (pFunK), which revealed functionally relevant Kbhb sites on various proteins, including aldolase B (ALDOB) Lys108. KD consumption or ß-hydroxybutyrate supplementation in hepatocellular carcinoma cells increases ALDOB Lys108bhb and inhibits the enzymatic activity of ALDOB. A Kbhb-mimicking mutation (p.Lys108Gln) attenuates ALDOB activity and its binding to substrate fructose-1,6-bisphosphate, inhibits mammalian target of rapamycin signalling and glycolysis, and markedly suppresses cancer cell proliferation. Our study reveals a critical role of Kbhb in regulating cancer cell metabolism and provides a generally applicable algorithm for predicting functionally important lysine modification sites.

NIR-II Light-Actuated Nanomotors for Enhanced Photoimmunotherapy Toward Hepatocellular Carcinoma.

Light-propelled nanomotors, which can convert external light into mechanical motion, have shown considerable potential in the construction of a new generation of drug delivery systems. However, the therapeutic efficacy of light-driven nanomotors is always unsatisfactory due to the limited penetration depth of near-infrared-I (NIR-I) light and the inherent biocompatibility of the motor itself. Herein, an asymmetric nanomotor (Pd@ZIF-8/R848@M JNMs) with efficient motion capability is successfully constructed for enhanced photoimmunotherapy toward hepatocellular carcinoma. Under near-infrared-II (NIR-II) irradiation, Pd@ZIF-8/R848@M JNMs convert light energy into heat energy, exhibiting self-thermophoretic locomotion to penetrate deeper into tumor tissues to achieve photothermal therapy. At the same time, functionalized with an immune-activated agent Resiquimod (R848), our nanomotors could convert a "cold tumor" into a "hot tumor", transforming the immunosuppressive microenvironment into an immune-activated state, thus achieving immunotherapy. Dual photoimmunotherapy of the as-developed NIR-II light-driven Pd@ZIF-8/R848@M JNMs demonstrates considerable tumor inhibition effects, offering a promising therapeutic approach in the field of anticancer therapy.

Bottle Nanomotors Amplify Tumor Oxidative Stress for Enhanced Calcium Overload/Chemodynamic Therapy.

Developing multifunctional, stimuli-responsive nanomedicine is intriguing because it has the potential to effectively treat cancer. Yet, poor tumor penetration of nanodrugs results in limited antitumor efficacy. Herein, an oxygen-driven silicon-based nanomotor (Si-motor) loaded with MnO and CaO2 nanoparticles is developed, which can move in tumor microenvironment (TME) by the cascade reaction of CaO2 and MnO. Under acidic TME, CaO2 reacts with acid to release Ca2+ to induce mitochondrial damage and simultaneously produces O2 and H2O2, when the loaded MnO exerts Fenton-like activity to produce ·OH and O2 based on the produced H2O2. The generated O2 drives Si-motor forward, thus endowing active delivery capability of the formed motors in TME. Meanwhile, MnO with glutathione (GSH) depletion ability further prevents reactive oxygen species (ROS) from being destroyed. Such TME actuated Si-motor with enhanced cellular uptake and deep penetration provides amplification of synergistic oxidative stresscaused by intracellular Ca2 + overloading, GSH depletion induced by Mn2+, and Mn2+ mediated chemodynamic treatment (CDT), leading to excellent tumor cell death. The created nanomotor may offer an effective platform for active synergistic cancer treatment.

Macrophage biomimetic nanoparticle-targeted functional extracellular vesicle micro-RNAs revealed via multiomics analysis alleviate sepsis-induced acute lung injury.

Patients who suffer from sepsis typically experience acute lung injury (ALI). Extracellular vesicles (EVs) contain miRNAs, which are potentially involved in ALI. However, strategies to screen more effective EV-miRNAs as therapeutic targets are yet to be elucidated. In this study, functional EV-miRNAs were identified based on multiomics analysis of single-cell RNA sequencing of targeted organs and serum EV (sEV) miRNA profiles in patients with sepsis. The proportions of neutrophils and macrophages were increased significantly in the lungs of mice receiving sEVs from patients with sepsis compared with healthy controls. Macrophages released more EVs than neutrophils. MiR-125a-5p delivery by sEVs to lung macrophages inhibited Tnfaip3, while miR-221-3p delivery to lung neutrophils inhibited Fos. Macrophage membrane nanoparticles (MM NPs) loaded with an miR-125a-5p inhibitor or miR-221-3p mimic attenuated the response to lipopolysaccharide (LPS)-induced ALI. Transcriptome profiling revealed that EVs derived from LPS-stimulated bone marrow-derived macrophages (BMDMs) induced oxidative stress in neutrophils. Blocking toll-like receptor, CXCR2, or TNFα signaling in neutrophils attenuated the oxidative stress induced by LPS-stimulated BMDM-EVs. This study presents a novel method to screen functional EV-miRNAs and highlights the pivotal role of macrophage-derived EVs in ALI. MM NPs, as delivery systems of key sEV-miRNA mimics or inhibitors, alleviated cellular responses observed in sepsis-induced ALI. This strategy can be used to reduce septic organ damage, particularly lung damage, by targeting EVs.

Light-Driven Biomimetic Nanomotors for Enhanced Photothermal Therapy.

Nanotechnology-based strategy has recently drawn extensive attention for the therapy of malignant tumors due to its distinct strengths in cancer diagnosis and treatment. However, the limited intratumoral permeability of nanoparticles is a major hurdle to achieving the desired effect of cancer treatment. Due to their superior cargo towing and reliable penetrating property, micro-/nanomotors (MNMs) are considered as one of the most potential candidates for the coming generation of drug delivery platforms. Here, near-infrared (NIR)-actuated biomimetic nanomotors (4T1-JPGSs-IND) are fabricated successfully and we demonstrate that 4T1-JPGSs-IND selectively accumulate in homologous tumor regions due to the effective homing ability. Upon laser irradiation, hyperthermia generated by 4T1-JPGSs-IND leads to self-thermophoretic motion and photothermal therapy (PTT) to ablate tumors with a deep depth, thereby improving the photothermal therapeutic effect for cancer management. The developed nanomotor system with multifunctionalities exhibits promising potential in biomedical applications to fight against various diseases.

A NIR-driven green affording-oxygen microrobot for targeted photodynamic therapy of tumors.

Photodynamic therapy (PDT) is a light-activated local treatment modality that has promising potential in cancer therapy. However, ineffective delivery of photosensitizers and hypoxia in the tumor microenvironment severely restrict the therapeutic efficacy of PDT. Herein, phototactic Chlorella (C) is utilized to carry photosensitizer-encapsulated nanoparticles to develop a near-infrared (NIR) driven green affording-oxygen microrobot system (CurNPs-C) for enhanced PDT. Photosensitizer (curcumin, Cur) loaded nanoparticles are first synthesized and then covalently attached to C through amide bonds. An in vitro study demonstrates that the developed CurNPs-C exhibits continuous oxygen generation and desirable phototaxis under NIR treatment. After intravenous injection, the initial 660 nm laser irradiation successfully induces the active migration of CurNPs-C to tumor sites for higher accumulation. Upon the second 660 nm laser treatment, CurNPs-C produces abundant oxygen, which in turn induces the natural product Cur to generate more reactive oxygen species (ROS) that significantly inhibit the growth of tumors in 4T1 tumor-bearing mice. This contribution showcases the ability of a light-driven green affording-oxygen microrobot to exhibit targeting capacity and O2 generation for enhancing photodynamic therapy.

Bladder microenvironment actuated proteomotors with ammonia amplification for enhanced cancer treatment.

Enzyme-driven micro/nanomotors consuming in situ chemical fuels have attracted lots of attention for biomedical applications. However, motor systems composed by organism-derived organics that maximize the therapeutic efficacy of enzymatic products remain challenging. Herein, swimming proteomotors based on biocompatible urease and human serum albumin are constructed for enhanced antitumor therapy via active motion and ammonia amplification. By decomposing urea into carbon dioxide and ammonia, the designed proteomotors are endowed with self-propulsive capability, which leads to improved internalization and enhanced penetration in vitro. As a glutamine synthetase inhibitor, the loaded l-methionine sulfoximine further prevents the conversion of toxic ammonia into non-toxic glutamine in both tumor and stromal cells, resulting in local ammonia amplification. After intravesical instillation, the proteomotors achieve longer bladder retention and thus significantly inhibit the growth of orthotopic bladder tumor in vivo without adverse effects. We envision that the as-developed swimming proteomotors with amplification of the product toxicity may be a potential platform for active cancer treatment.

Cancer Cell Membrane-Coated Nanoparticle Co-loaded with Photosensitizer and Toll-like Receptor 7 Agonist for the Enhancement of Combined Tumor Immunotherapy.

Tumor immunotherapy has shown considerable therapeutic potential in the past few years, but the clinical response rate of immunotherapy is less than 20%. Encountering the high heterogeneity of tumors, it will be a general trend to apply combined therapy for cancer treatment. Photodynamic therapy (PDT) transiently kills tumor cells by producing reactive oxygen species (ROS), while residual tumor cells are prone to metastasis, leading to tumor recurrence. In combination with tumor immunotherapy, it is hoped to awaken the host immune system and eradicate residual tumor cells. Herein, cancer cell membrane-coated nanoparticles as a platform to combine PDT, TLR7 agonist, and tumor antigen for the enhancement of tumor therapeutic efficacy are designed. The final biomimetic nanoparticles (CCMV/LTNPs) can specifically kill tumor cells through PDT, while strong host antitumor immune responses are elicited to eliminate residue tumor cells under the help of immune adjuvant and tumor antigen from the cancer cell membrane. In summary, a photoimmunotherapy strategy is designed that synergistically enhances the tumor therapeutic effects by killing tumor cells through PDT and activating host antitumor immune responses through the co-delivery of adjuvant and tumor antigen, which may offer a promising strategy for clinical immunotherapy in the future.

Hyperthermia-triggered biomimetic bubble nanomachines.

Nanoparticle-based drug delivery systems have gained much attention in the treatment of various malignant tumors during the past decades. However, limited tumor penetration of nanodrugs remains a significant hurdle for effective tumor therapy due to the existing biological barriers of tumoral microenvironment. Inspired by bubble machines, here we report the successful fabrication of biomimetic nanodevices capable of in-situ secreting cell-membrane-derived nanovesicles with smaller sizes under near infrared (NIR) laser irradiation for synergistic photothermal/photodynamic therapy. Porous Au nanocages (AuNC) are loaded with phase transitable perfluorohexane (PFO) and hemoglobin (Hb), followed by oxygen pre-saturation and indocyanine green (ICG) anchored 4T1 tumor cell membrane camouflage. Upon slight laser treatment, the loaded PFO undergoes phase transition due to surface plasmon resonance effect produced by AuNC framework, thus inducing the budding of outer cell membrane coating into small-scale nanovesicles based on the pore size of AuNC. Therefore, the hyperthermia-triggered generation of nanovesicles with smaller size, sufficient oxygen supply and anchored ICG results in enhanced tumor penetration for further self-sufficient oxygen-augmented photodynamic therapy and photothermal therapy. The as-developed biomimetic bubble nanomachines with temperature responsiveness show great promise as a potential nanoplatform for cancer treatment.

Directed Neural Stem Cells Differentiation via Signal Communication with Ni-Zn Micromotors.

Neural stem cells (NSCs), with the capability of self-renewal, differentiation, and environment modulation, are considered promising for stroke, brain injury therapy, and neuron regeneration. Activation of endogenous NSCs, is attracting increasing research enthusiasm, which avoids immune rejection and ethical issues of exogenous cell transplantation. Yet, how to induce directed growth and differentiation in situ remain a major challenge. In this study, a pure water-driven Ni-Zn micromotor via a self-established electric-chemical field is proposed. The micromotors can be magnetically guided and precisely approach target NSCs. Through the electric-chemical field, bioelectrical signal exchange and communication with endogenous NSCs are allowed, thus allowing for regulated proliferation and directed neuron differentiation in vivo. Therefore, the Ni-Zn micromotor provides a platform for controlling cell fate via a self-established electrochemical field and targeted activation of endogenous NSCs.

Tyrosine kinase inhibitors and atherosclerosis: A close but complicated relationship.

Targeted cancer therapies have revolutionized the treatment of the disease in the past decade. The tyrosine kinase inhibitor (TKI) class of drugs is a widely used option for treating various cancers. Despite numerous advances, clinical and experimental studies have demonstrated the atherosclerosis-inducing properties of these drugs that can cause adverse cardiovascular events. TKIs also have an atherosclerosis-preventing role in patients with cancer through different mechanisms under various conditions, suggesting that specific drugs play different roles in atherosclerosis regulation. Given these contradictory properties, this review summarizes the outcomes of previously performed clinical and basic experiments and shows how the targeted effects of novel TKIs affect atherosclerosis. Future collaborative efforts are warranted to enhance our understanding of the association between TKIs and atherosclerosis.

Magnetically Actuated Biodegradable Nanorobots for Active Immunotherapy.

An efficient and cost-effective therapeutic vaccine is highly desirable for the prevention and treatment of cancer, which helps to strengthen the immune system and activate the T cell immune response. However, initiating such an adaptive immune response efficiently remains challenging, especially the deficient antigen presentation by dendritic cells (DCs) in the immunosuppressive tumor microenvironment. Herein, an efficient and dynamic antigen delivery system based on the magnetically actuated OVA-CaCO3 -SPIO robots (OCS-robots) is rationally designed for active immunotherapy. Taking advantage of the unique dynamic features, the developed OCS-robots achieve controllable motion capability under the rotating magnetic field. Specifically, with the active motion, the acid-responsiveness of OCS-robots is beneficial for the tumor acidity attenuating and lysosome escape as well as the subsequent antigen cross-presentation of DCs. Furthermore, the dynamic OCS-robots boost the crosstalk between the DCs and antigens, which displays prominent tumor immunotherapy effect on melanoma through cytotoxic T lymphocytes (CTLs). Such a strategy of dynamic vaccine delivery system enables the active activation of immune system based on the magnetically actuated OCS-robots, which presents a plausible paradigm for incredibly efficient cancer immunotherapy by designing multifunctional and novel robot platforms in the future.

Medical micro- and nanomotors in the body.

Attributed to the miniaturized body size and active mobility, micro- and nanomotors (MNMs) have demonstrated tremendous potential for medical applications. However, from bench to bedside, massive efforts are needed to address critical issues, such as cost-effective fabrication, on-demand integration of multiple functions, biocompatibility, biodegradability, controlled propulsion and in vivo navigation. Herein, we summarize the advances of biomedical MNMs reported in the past two decades, with particular emphasis on the design, fabrication, propulsion, navigation, and the abilities of biological barriers penetration, biosensing, diagnosis, minimally invasive surgery and targeted cargo delivery. Future perspectives and challenges are discussed as well. This review can lay the foundation for the future direction of medical MNMs, pushing one step forward on the road to achieving practical theranostics using MNMs.

Immunostimulant In Situ Fibrin Gel for Post-operative Glioblastoma Treatment by Macrophage Reprogramming and Photo-Chemo-Immunotherapy.

Tumor recurrence remains the leading cause of treatment failure following surgical resection of glioblastoma (GBM). M2-like tumor-associated macrophages (TAMs) infiltrating the tumor tissue promote tumor progression and seriously impair the efficacy of chemotherapy and immunotherapy. In addition, designing drugs capable of crossing the blood-brain barrier and eliciting the applicable organic response is an ambitious challenge. Here, we propose an injectable nanoparticle-hydrogel system that uses doxorubicin (DOX)-loaded mesoporous polydopamine (MPDA) nanoparticles encapsulated in M1 macrophage-derived nanovesicles (M1NVs) as effectors and fibrin hydrogels as in situ delivery vehicles. In vivo fluorescence imaging shows that the hydrogel system triggers photo-chemo-immunotherapy to destroy remaining tumor cells when delivered to the tumor cavity of a model of subtotal GBM resection. Concomitantly, the result of flow cytometry indicated that M1NVs comprehensively improved the immune microenvironment by reprogramming M2-like TAMs to M1-like TAMs. This hydrogel system combined with a near-infrared laser effectively promoted the continuous infiltration of T cells, restored T cell effector function, inhibited the infiltration of myeloid-derived suppressor cells and regulatory T cells, and thereby exhibited a strong antitumor immune response and significantly inhibited tumor growth. Hence, MPDA-DOX-NVs@Gel (MD-NVs@Gel) presents a unique clinical strategy for the treatment of GBM recurrence.

Advanced imaging modalities provide new insights into coronary artery calcification.

Coronary calcification plays a major role as a key surrogate measure of plaque burden, providing powerful risk stratification and influencing preventive therapy. Depending on its location and density, microcalcifications may directly result in plaque rupture and adverse clinical events. Although macroscopic calcifications are frequently linked to advanced and stable plaques, the fact that a small number of thrombotic events are caused by plaques that possess a substantial amount of calcification should not be overlooked. Early and accurate assessment of calcium content in atherosclerotic plaques potentially enhances the identification of high-risk patients requiring preventive treatments. Non-invasive imaging allows for the visualization, detection, and quantification of calcific lesions, whereas intravascular imaging has the unique advantage of providing real-time and accurate information during calcium modification interventions. Simultaneously, emerging molecular imaging modalities aid in the investigation of calcification activity. This review summarizes advanced techniques for coronary artery calcification imaging, including their merits and limitations, in addition to their potential applications in both experimental and clinical settings.

Micro-Nano Motors with Taxis Behavior: Principles, Designs, and Biomedical Applications.

As a novel mobile nanodevice, micro-nano motors (MNMs) can convert the energy of the surrounding environment into mechanical motion. With this unique ability, they promise revolutionary potential in bio-applications including precise drug delivery, bio-sensing, and noninvasive surgery. Yet for practically reaching the target and fulfilling these tasks in dynamically changing bio-environment, environment adaptivity beyond propulsion is important yet challenging. MNMs with taxis behavior/autonomous target-seeking ability offer a desirable solution. These motors can adaptively move to the target location and complete the task. Thanks to the persistent efforts of researchers, tactic MNMs have shown automatic navigation to target under various energy fields, not only in static environments, but also in shear rheological conditions that simulate blood flow. Therefore, tactic motors with self-targeting capability lay a concrete foundation for targeted drug delivery, cell transplantation, and thrombus ablation. This review systematically presents the moving principle, design, and biological applications of tactic MNMs under different energy fields. Through in-depth analysis of state-of-art progress, the obstacles of the field and possible solutions are discussed. With the continuous innovation and breakthroughs of multi-disciplinary researchers, MNMs with taxis behavior are expected to provide a revolutionary solution for cancer and other major diseases in the biomedical field.

Autophagy-inhibiting biomimetic nanodrugs enhance photothermal therapy and boost antitumor immunity.

The instinctive protective stress responses of tumor cells hamper low-temperature photothermal therapy (LTPTT), resulting in tumor recurrence and metastasis. The rapid blood clearance and low-efficiency tumor enrichment of nanomedicines also decrease the efficacy of LTPTT. In this study, we fabricated coassembled photothermal agents (indocyanine green, ICG) and autophagy inhibitors (chloroquine, CQ) and red blood cell and cancer cell hybrid membrane (RCm)-camouflaged ICGCQ@RCm nanoparticles (ICGCQ@RCm NPs) to enhance tumor LTPTT. The ICGCQ@RCm NPs exhibited prolonged blood drug circulation and markedly enhanced drug accumulation in tumor tissues. The ICGCQ@RCm NPs reduced the thermal tolerance of tumor cells to sensitize ICG-mediated LTPTT by inhibiting protective autophagy. The ICGCQ@RCm NPs exerted strong immunogenic cell death (ICD) after efficient LTPTT to activate antitumor immunity. In addition, ICGCQ@RCms optimized the therapeutic efficacy by imaging-guided LTPTT, taking advantage of the near-infrared (NIR) fluorescence of ICG. Consequently, the ICGCQ@RCm NPs effectively inhibited tumors under mild LTPTT, significantly suppressed tumor metastasis and prolonged the survival time of tumor-bearing mice. Furthermore, the ICGCQ@RCm NPs showed high biosafety in vitro and in vivo. The ICGCQ@RCm NPs demonstrated tumor-targeting and imaging-guided autophagy inhibition-sensitized LTPTT using two Food and Drug Administration (FDA)-approved drugs, which have great potential for clinical application.

Apoptotic Tumor DNA Activated Nanomotor Chemotaxis.

Inspired by the tactic organisms in Nature that can self-direct their movement following environmental stimulus gradient, we proposed a DNase functionalized Janus nanoparticle (JNP) nanomotor system for the first time, which can be powered by ultralow nM to µM levels of DNA. The system exhibited interesting chemotactic behavior toward a DNA richer area, which is physiologically related with many diseases including tumors. In the presence of the subtle DNA gradient generated by apoptotic tumor cells, the cargo loaded nanomotors were able to sense the DNA signal released by the cells and demonstrate directional motion toward tumor cells. For our system, the subtle DNA gradient by a small amount (10 µL) of tumor cells is sufficient to induce the chemotaxis behavior of self-navigating and self-targeting ability of our nanomotor system, which promises to shed new light for tumor diagnosis and therapy.

MnO2-Based Nanomotors with Active Fenton-like Mn2+ Delivery for Enhanced Chemodynamic Therapy.

Chemodynamic therapy (CDT) is an emerging strategy for cancer treatment based on Fenton chemistry, which can convert endogenous H2O2 into toxic ·OH. However, the limited endocytosis of passive CDT nanoagents with low penetrating capability resulted in unsatisfactory anticancer efficacy. Herein, we propose the successful fabrication of a self-propelled biodegradable nanomotor system based on hollow MnO2 nanoparticles with catalytic activity for active Fenton-like Mn2+ delivery and enhanced CDT. Compared with the passive counterparts, the significantly improved penetration of nanomotors with enhanced diffusion is demonstrated in both the 2D cell culture system and 3D tumor multicellular spheroids. After the intracellular uptake of nanomotors, toxic Fenton-like Mn2+ is massively produced by consuming overexpressed intracellular glutathione (GSH), which has a strong scavenging effect on ·OH, thereby leading to enhanced cancer CDT. The as-developed MnO2-based nanomotor system with enhanced penetration and endogenous GSH scavenging capability shows much promise as a potential platform for cancer treatment in the near future.