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Radiation-induced heart disease (RIHD), characterized by severe oxidative stress and immune dysregulation, is a serious condition affecting cancer patients undergoing thoracic radiation. Unfortunately, clinical interventions for RIHD are lacking. Selenium (Se) is a trace element with excellent antioxidant and immune-modulatory properties. However, its application in heart radioprotection remains challenging. Herein, we developed a novel bioactive Cordyceps militaris-based Se oral delivery system (Se@CM), which demonstrated superior radioprotection effects in vitroagainst X-ray-induced damage in H9C2 cells through suppressing excessive ROS generation, compared to the radioprotectant Amifostine. Moreover, Se@CMexhibited exceptional cardioprotective effects in vivoagainst X-ray irradiation, reducing cardiac dysfunction and myocardial fibrosis by balancing the redox equilibrium and modulating the expression of Mn-SOD and MDA. Additionally, Se@CMmaintained immuno-homeostasis, as evidenced by the upregulated population of T cells and M2 macrophages through modulation of selenoprotein expression after irradiation. Together, these results highlight the remarkable antioxidant and immunity modulation properties of Se@CMand shed light on its promising application for cardiac protection against IR-induced disease. This research provides valuable insights into developing effective strategies for preventing and managing RIHD.

The augmented intra-operative real-time imaging in vascular interventional surgery, which is generally performed by projecting preoperative computed tomography angiography images onto intraoperative digital subtraction angiography (DSA) images, can compensate for the deficiencies of DSA-based navigation, such as lack of depth information and excessive use of toxic contrast agents. 3D/2D vessel registration is the critical step in image augmentation. A 3D/2D registration method based on vessel graph matching is proposed in this study. For rigid registration, the matching of vessel graphs can be decomposed into continuous states, thus 3D/2D vascular registration is formulated as a search tree problem. The Monte Carlo tree search method is applied to find the optimal vessel matching associated with the highest rigid registration score. For nonrigid registration, we propose a novel vessel deformation model based on manifold regularization. This model incorporates the smoothness constraint of vessel topology into the objective function. Furthermore, we derive simplified gradient formulas that enable fast registration. The proposed technique undergoes evaluation against seven rigid and three nonrigid methods using a variety of data - simulated, algorithmically generated, and manually annotated - across three vascular anatomies: the hepatic artery, coronary artery, and aorta. Our findings show the proposed method’s resistance to pose variations, noise, and deformations, outperforming existing methods in terms of registration accuracy and computational efficiency. The proposed method demonstrates average registration errors of 2.14 mm and 0.34 mm for rigid and nonrigid registration, and an average computation time of 0.51 s.

Chlorambucil (Cbl) is a DNA alkylating drug in the nitrogen mustard family, but the clinical applications of nitrogen mustard antitumor drugs are frequently limited by their poor aqueous solubility, poor cellular uptake, lack of targeting, and severe side effects. Additionally, mitochondria are the energy factories for cells, and tumor cells are more susceptible to mitochondrial dysfunction than some healthy cells, thus making mitochondria an important target for tumor therapy. As a proof-of-concept, direct delivery of Cbl to tumor cells’ mitochondria will probably bring about new opportunities for the nitrogen mustard family. Furthermore, IR775 chloride is a small-molecule lipophilic cationic heptamethine cyanine dye with potential advantages of mitochondria targeting, near-infrared (NIR) fluorescence imaging, and preferential internalization towards tumor cells. Here, an amphiphilic drug conjugate was facilely prepared by covalently coupling chlorambucil with IR775 chloride and further self-assembly to form a carrier-free self-delivery theranostic system, in which the two components are both functional units aimed at theranostic improvement. The theranostic IR775-Cbl potentiated typical “1 + 1 > 2” tumor inhibition through specific accumulation in mitochondria, which triggered a remarkable decrease in mitochondrial membrane potential and ATP generation. In vivobiodistribution and kinetic monitoring were achieved by real-time NIR fluorescence imaging to observe its transport inside a living body. Current facile mitochondria-targeting modification with clinically applied drugs was promising for endowing traditional drugs with targeting, imaging, and improved potency in disease theranostics.

N6-methyladenosine (m6A), the most common and abundant epigenetic RNA modification, governs mRNA metabolism to determine cell differentiation, proliferation and response to stimulation. m6A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells (Tregs). However, the role of m6A methyltransferase in other subtypes of T cells remains unknown. T helper cells 17 (Th17) play a pivotal role in host defense and autoimmunity. Here, we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation, and impeded the development of experimental autoimmune encephalomyelitis (EAE). We generated Mettl3f/fIl17aCremice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system (CNS). Importantly, we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells, leading to disrupted Th17 cell differentiation and infiltration, and eventually attenuating the process of EAE. Collectively, our results highlight that m6A modification sustains Th17 cell function, which provides new insights into the regulatory network of Th17 cells, and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.

Imaging-guided percutaneous microwave thermotherapy has been regarded as an important alternative nonsurgical therapeutic strategy for hepatocellular carcinoma (HCC) that provides excellent local tumor control and favorable survival benefit. However, providing a high-resolution, real-time, and noninvasive imaging technique for intraoperative guidance and controlling postoperative residual tumor recurrence are urgent needs for the clinical setting. In this study, a cisplatin (CDDP)-loaded nanocapsule (NPs@CDDP) with microwave responsive property was prepared to simultaneously serve as a contrast agent of emerging thermoacoustic imaging and a sensitizing agent of microwave thermo-chemotherapy. Accompanying the enzymolysis in the tumor microenvironment, the NPs@CDDP responsively release l-arginine (l-Arg) and CDDP. l-Arg with excellent microwave-absorbing property allowed it to serve as a thermoacoustic imaging contrast agent for accurately delineating the tumor and remarkably increasing tumor temperature under ultralow power microwave irradiation. Apart from the chemotherapeutic effect, CDDP elevated the intracellular H2O2level through cascade reactions and further accelerated the continuous transformation of l-Arg to nitric oxide (NO), which endowed the NPs@CDDP with NO-generation capability. Notably, the high concentration of intracellular NO was proved to aggravate lipid peroxidation and greatly improved the efficacy of microwave thermo-chemotherapy. Thereby, NPs@CDDP was expected to serve as a theranostic agent integrating the functions of tumor microenvironment-responsive drug delivery system, contrast agent of thermoacoustic imaging, thermal sensitizing agent, and NO nanogenerator, which was promising to provide a potential imaging-guided therapeutic strategy for HCC.

Although the Hedgehog (Hh) pathway plays an evolutionarily conserved role from Drosophilato mammals, some divergences also exist. Loss of Sufu, an important component of the Hh pathway, does not lead to an obvious developmental defect in Drosophila. However, in mammals, loss of SUFU results in serious disorder, even various cancers. This divergence suggests that SUFU plays additional roles in mammalian cells, besides regulating the Hh pathway. Here, we identify that the transcription factor ZNF281 is a novel binding partner of SUFU. Intriguingly, the Drosophilagenome does not encode any homologs of ZNF281. SUFU is able to suppress ZNF281-induced tumor cell migration and DNA damage repair by inhibiting ZNF281 activity. Mechanistically, SUFU binds ZNF281 to mask the nuclear localization signal of ZNF281, culminating in ZNF281 cytoplasmic retention. In addition, SUFU also hampers the interactions between ZNF281 and promoters of target genes. Finally, we show that SUFU is able to inhibit ZNF281-induced tumor cell migration using an in vivo model. Taken together, these results uncover a Hh-independent mechanism of SUFU exerting the anti-tumor role, in which SUFU suppresses tumor cell migration through antagonizing ZNF281. Therefore, this study provides a possible explanation for the functional divergence of SUFU in mammals and Drosophila.

Nowadays, with the rapid development of artificial intelligence, conductive hydrogel-based sensors play an increasingly vital role in health monitoring and temperature sensing. However, the perfect integration of the environmental stability and applied performance of the hydrogel has always been a challenging and significant problem. Herein, we report an environmentally tolerant, stretchable, adhesive, self-healing conductive gel through multiple dynamic interactions in the water/glycerol/ionic liquids medium, which can be used as a high-performance strain and temperature sensor. The random copolymer poly(acrylic acid-co-acetoacetoxyethyl methacrylate) interacts with the branched poly(ethylene imine) (PEI) and Zr4+ions via the dynamic covalent enamine bonds, coordinations, and electrostatic interactions to improve stretchable (1300%), compressible, fatigue-resistant (1000 cycles at 50% strain), and self-healing performance (95%, 24 h). The combination of water/glycerol/ionic liquids imparts the resulting gel with excellent electrical conductivity, anti-drying, and anti-freezing performance. By means of the above excellent performance, the gel could be used as the flexible strain or pressure sensor with high sensitivity and stability for the detection of the movement, expression, handwriting, pronouncing, and electrocardiogram (ECG) signals in various models. Meanwhile, the resulting gel can be assembled as the temperature sensor to trace the change of temperature accurately and steadily, which has a wide operating window (0 to 100 °C), an ultralow detection limit (0.2 °C), and high sensitivity (2.1% °C–1). It is believed that the strategy for the multifunction and high-performance gel will blaze a new trail for the smart device in health management, temperature detection, and information transmission under various environmental conditions.

Immune-checkpoint inhibitor-based combination immunotherapy has become a first-line treatment for several major types of cancer including hepatocellular carcinoma (HCC), renal cell carcinoma, lung cancer, cervical cancer, and gastric cancer. Combination immunotherapy counters several immunosuppressive elements in the tumor microenvironment and activates multiple steps of the cancer-immunity cycle. The anti-PD-L1 antibody, atezolizumab, plus the anti-vascular endothelial growth factor antibody, bevacizumab, represents a promising class of combination immunotherapy. This combination has produced unprecedented clinical efficacy in unresectable HCC and become a landmark in HCC therapy. Advanced HCC patients treated with atezolizumab plus bevacizumab demonstrated impressive improvements in multiple clinical endpoints including overall survival, progress-free survival, objective response rate, and patient-reported quality of life when compared to current first-line treatment with sorafenib. However, atezolizumab plus bevacizumab first-line therapy has limitations. First, cancer patients falling into the criteria for the combination therapy may need to be further selected to reap benefits while avoiding some potential pitfalls. Second, the treatment regimen of atezolizumab plus bevacizumab at a fixed dose may require adjustment for optimal normalization of the tumor microenvironment to obtain maximum efficacy and reduce adverse events. Third, utilization of predictive biomarkers is urgently needed to guide the entire treatment process. Here we review the current status of clinically approved combination immunotherapies and the underlying immune mechanisms. We further provide a perspective analysis of the limitations for combination immunotherapies and potential approaches to overcome the limitations.

Smart transformable nanocarriers are promising to treat deep-seated diseases but require adaptable diagnostic/imaging potency to reflect the morphology change and therapeutic feedback, yet their design and synthesis remains challenging. Herein, stimuli-responsive polyprodrug nanoparticles (SPNs) are formulated from the co-assembly of negatively charged corona and positively charged polyprodrug cores, exhibiting high loading content of camptothecin (CPT, ∼28.6 wt %) tethered via disulfide linkages in the core. SPNs are sequentially sensitive to tumor acidic condition and elevated reductive milieu in the cytosol for deep-penetration drug delivery. Upon accumulation at acidic tumor sites, SPNs dissociate to release smaller positively charged polyprodrug nanoparticles, which efficiently enter deep-seated tumor cells to trigger high-dosage parent CPT release in the reductive cytosolic milieu. Meanwhile, the polyprodrug cores of SPNs labeled with DTPA(Gd), a magnetic resonance imaging contrast agent, can trace the cascade degradation and biodistribution of SPNs as well as the resulting intracellular CPT release. The longitudinal relaxivity of SPNs increases stepwise in the above two processes. The size-switchable polyprodrug nanoparticles exhibit remarkable tumor penetration and noteworthy tumor inhibition in vitroand in vivo, which are promising for endogenously activated precision diagnostics and therapy.

Biofilm can protect bacteria from immune attacks and antibiotic inhibition, and bacterial biofilm hosted in implanted materials and medical devices is a serious threat for modern medical system. Herein, we report biofilm-responsive caged guanidine nanoparticles (CGNs) to deeply penetrate and accumulate in bacterial biofilm, and then efficient photothermal eradication of bacterial biofilm is achieved upon NIR laser irradiation via the proof-of-concept formulation of photothermal agents in CGNs. In physiological conditions and blood circulation, CGNs are negatively charged by masking the positive charge of guanidine via covalent modification with acid-cleavable moieties, exhibiting high biocompatibility and minimal hemolysis. Whereas upon blood circulation and passive accumulation at infected implant sites, CGNs are self-adaptive in acidic biofilm to release the protective caging group and expose native guanidine moieties, which can promote nanoparticle deep biofilm penetration and bacteria adhesion as well as membrane fusion. After that, remarkable photothermal effect with a high photothermal conversion efficiency of ∼40.9% can eradicate implant biofilm upon NIR laser irradiation. It can efficiently treat S. aureusbiofilm-infected implant catheters in vivovia only one single treatment in a mouse model, exhibiting ∼99.6% bacteria inhibition ratio. Apart from this proof-of-concept work, current guanidine-caged biofilm responsive polymeric nanoparticles are promising general vectors to treat biofilm and resistant pathogens in medicine and daily healthcare.

A broad-spectrum polymeric antimicrobial, PEoS-PHMG, was developed to achieve dual-modality bacterial inhibition viaphotodynamic inactivation and physical damage. Compared with native PHMG, current photosensitizer conjugate-functionalized PHMG exhibited excellent bacterial inhibition and enhanced biocompatibility with minimal cytotoxicity toward mammalian cells.

Many metal complexes not only had excellent cytotoxic antitumor effects but also could function as a positive immunomodulatory to improve antitumor effects by modifying the local tumor microenvironment. Herein, a dual-target nanotherapeutics (MP3/ACPP/AE105@NPs) with uPAR targeting and tumor microenvironment-responsive ability was developed by using AE105 as the targeting ligand and ACPP as the tumor microenvironment-responsive peptide to locate the metal complex to cells. Assisted by the surface modification, MP3/ACPP/AE105@NPs demonstrated excellent cellular uptake of the drugs in in vitro experiments, thereby enhancing the therapeutic utility of the loaded metal complex. The nanotherapeutics induced the excessive ROS generation by inhibiting the activity of TrxR and modulated those proteins which were related to metastasis through inhibiting ERK/AKT activation mediated by FAK in MDA-MB-231 cells. This nanotherapeutics could also significantly improve the therapeutic benefits in vivo accompanied by reduced toxic side effects. Importantly, MP3/ACPP/AE105@NPs treatment stimulated immunotherapeutic response, which was indicated by the activation of tumor-infiltrated cytotoxic T cells, and improved the maturation of dendritic cells (DCs), and the proliferation-inhibitory effect of tumor-associated M2 macrophages. Taken together, the results suggested that this dual-targeted nanotherapeutics offered new opportunities for boosting the synergistic treatment of breast cancer with chemotherapy and immunotherapy.

ABSTRACTVaccines are urgently needed to control the COVID-19 pandemic. To gradually increase the vaccination rate among residents, temporary vaccination clinic for COVID-19 plays an important role. It should be located in an area with convenient transportation and concentrated population. Functional zones including waiting and inquiry, registration and notification, injection, observation and emergency room should be established. All vaccine recipients’ information should be uploaded to the national immunization information system. Medical staff at the temporary vaccination clinic should be professionally trained. A cautious disinfection and wiping are essential for the temporary vaccination clinic.

Cancer radiation therapy (RT) is limited by endogenous DNA repair of tumor cells and microenvironmental hypoxia in tumor tissues. Herein, we demonstrated an effective cancer chemo-radiotherapy strategy based on choline phosphate liposomal nanomedicines, which inhibit the intrinsic radioresistance of RT and concomitantly harness the RT-induced hypoxia to produce additional toxicity to overcome post-RT radioresistance. To achieve this strategy, a radiotherapy sensitizer, vorinostat, and a hypoxia-activated banoxantrone dihydrochloride (AQ4N) were simultaneously delivered to a tumor using liposomes composed of an inverted polarity lipid 2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl ethyl phosphate (DOCPe). The DOCPe liposomes exhibited a longer blood circulation time and enhanced tumor accumulation, compared to their zwitterionic phosphocholine counterpart. The RT was sensitized by vorinostat to kill non-tolerant normoxic tumor cells efficiently. The irradiation aggravated hypoxia-activated AQ4N to further potentiate RT treatment. This chemo-radiotherapy combination showed excellent tumor treatment efficacy and is promising for future clinical translation.