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High circulating levels of lactate and high mobility group box-1 (HMGB1) are associated with the severity and mortality of sepsis. However, it is unclear whether lactate could promote HMGB1 release during sepsis. The present study demonstrated a novel role of lactate in HMGB1 lactylation and acetylation in macrophages during polymicrobial sepsis. We found that macrophages can uptake extracellular lactate via monocarboxylate transporters (MCTs) to promote HMGB1 lactylation via a p300/CBP-dependent mechanism. We also observed that lactate stimulates HMGB1 acetylation by Hippo/YAP-mediated suppression of deacetylase SIRT1 and β-arrestin2-mediated recruitment of acetylases p300/CBP to the nucleus via G protein-coupled receptor 81 (GPR81). The lactylated/acetylated HMGB1 is released from macrophages via exosome secretion which increases endothelium permeability. In vivo reduction of lactate production and/or inhibition of GPR81-mediated signaling decreases circulating exosomal HMGB1 levels and improves survival outcome in polymicrobial sepsis. Our results provide the basis for targeting lactate/lactate-associated signaling to combat sepsis.

Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy is either increased or unchanged in old versus young mice. Transcriptomic analysis shows marked upregulation of the type I interferon response in the retina of old mice, which correlates with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations are replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuates cGAS/STING activation and ameliorates deterioration of neurological function. These findings point to mitophagy induction as a strategy to decrease age-associated inflammation and increase healthspan. Dysregulated autophagy and mitochondrial function are two well-described hallmarks of aging. Here, the authors describe an unexpected age-associated upregulation of mitophagy in response to neuroinflammation triggered by leaked mtDNA.

Circular RNAs (circRNAs) have been implicated in cancer progression through largely unknown mechanisms. Herein, we identify an N 6 -methyladenosine (m 6 A) modified circRNA, circNSUN2, frequently upregulated in tumor tissues and serum samples from colorectal carcinoma (CRC) patients with liver metastasis (LM) and predicts poorer patient survival. The upregulated expression of circNSUN2 promotes LM in PDX metastasis models in vivo and accelerates cancer cells invasion in vitro. Importantly, N 6 -methyladenosine modification of circNSUN2 increases export to the cytoplasm. By forming a circNSUN2/IGF2BP2/ HMGA2 RNA-protein ternary complex in the cytoplasm, circNSUN2 enhances the stability of HMGA2 mRNA to promote CRC metastasis progression. Clinically, the upregulated expressions of circNSUN2 and HMGA2 are more prevalent in LM tissues than in primary CRC tissues. These findings elucidate that N 6 -methyladenosine modification of circNSUN2 modulates cytoplasmic export and stabilizes HMGA2 to promote CRC LM, and suggest that circNSUN2 could represent a critical prognostic marker and/or therapeutic target for the disease. Liver metastasis of colorectal cancer leads to poor prognosis. Here the authors report that an N 6 -methyladenosine modified circular RNA is upregulated in colorectal cancer and promotes liver metastasis by enhancing the stability of HMGA2 mRNA.

Metabolic reprogramming is a hallmark of cancer. Here, we demonstrate that tumour-associated macrophages (TAMs) enhance the aerobic glycolysis and apoptotic resistance of breast cancer cells via the extracellular vesicle (EV) transmission of a myeloid-specific lncRNA, HIF-1α-stabilizing long noncoding RNA (HISLA). Mechanistically, HISLA blocks the interaction of PHD2 and HIF-1α to inhibit the hydroxylation and degradation of HIF-1α. Reciprocally, lactate released from glycolytic tumour cells upregulates HISLA in macrophages, constituting a feed-forward loop between TAMs and tumour cells. Blocking EV-transmitted HISLA inhibits the glycolysis and chemoresistance of breast cancer in vivo. Clinically, HISLA expression in TAMs is associated with glycolysis, poor chemotherapeutic response and shorter survival of patients with breast cancer. Our study highlights the potential of lncRNAs as signal transducers that are transmitted between immune and tumour cells via EVs to promote cancer aerobic glycolysis. Chen et al. show that tumour-associated macrophages transmit HIF-1α-stabilizing long noncoding RNA through extracellular vesicles to breast cancer cells, thereby enhancing tumour glycolysis and chemoresistance.

The treatment of diabetic wounds faces enormous challenges due to complex wound environments, such as infected biofilms, excessive inflammation, and impaired angiogenesis. The critical role of the microenvironment in the chronic diabetic wounds has not been addressed for therapeutic development. Herein, we develop a microneedle (MN) bandage functionalized with dopamine-coated hybrid nanoparticles containing selenium and chlorin e6 (SeC@PA), which is capable of the dual-directional regulation of reactive species (RS) generation, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), in response to the wound microenvironment. The SeC@PA MN bandage can disrupt barriers in wound coverings for efficient SeC@PA delivery. SeC@PA not only depletes endogenous glutathione (GSH) to enhance the anti-biofilm effect of RS, but also degrades GSH in biofilms through cascade reactions to generate more lethal RS for biofilm eradication. SeC@PA acts as an RS scavenger in wound beds with low GSH levels, exerting an anti-inflammatory effect. SeC@PA also promotes the M2-phenotype polarization of macrophages, accelerating wound healing. This self-enhanced, catabolic and dynamic therapy, activated by the wound microenvironment, provides an approach for treating chronic wounds. The treatment of diabetic wounds tends to be hindered by complex wound environments, and the critical role of the microenvironment in the chronic diabetic wounds has not been explored for therapeutic development. Here, the authors develop a wound microenvironment-responsive microneedle bandage to achieve self-enhanced, catabolic and dynamic therapy of chronic wounds.

Theranostic sonosensitizers with combined sonodynamic and near infrared (NIR) imaging modes are required for imaging guided sonodynamic therapy (SDT). It is challenging, however, to realize a single material that is simultaneously endowed with both NIR emitting and sonodynamic activities. Herein, we report the design of a class of NIR-emitting sonosensitizers from a NIR phosphorescent carbon dot (CD) material with a narrow bandgap (1.62 eV) and long-lived excited triplet states (11.4 μs), two of which can enhance SDT as thermodynamically and dynamically favorable factors under low-intensity ultrasound irradiation, respectively. The NIR-phosphorescent CDs are identified as bipolar quantum dots containing both p- and n-type surface functionalization regions that can drive spatial separation of e − –h + pairs and fast transfer to reaction sites. Importantly, the cancer-specific targeting and high-level intratumor enrichment of the theranostic CDs are achieved by cancer cell membrane encapsulation for precision SDT with complete eradication of solid tumors by single injection and single irradiation. These results will open up a promising approach to engineer phosphorescent materials with long-lived triplet excited states for sonodynamic precision tumor therapy. Combining sonodynamic properties and NIR fluorescence into a single material is desired for deep tissue applications. Here, the authors report on carbon dot sono-sensitizers engineered with a narrow bandgap and coated with cancer cell membrane for targeted NIR guided sonodynamic cancer therapy.

Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it. CD36 then gets depalmitoylated by APT1 and recruits another tyrosine kinase SYK to phosphorylate JNK and VAVs to initiate endocytic uptake of FAs. Blocking CD36 internalization by inhibiting APT1, LYN or SYK abolishes CD36-dependent FA uptake. Restricting CD36 at either palmitoylated or depalmitoylated state eliminates its FA uptake activity, indicating an essential role of dynamic palmitoylation of CD36. Furthermore, blocking endocytosis by targeting LYN or SYK inhibits CD36-dependent lipid droplet growth in adipocytes and high-fat-diet induced weight gain in mice. Our study has uncovered a dynamic palmitoylation-regulated endocytic pathway to take up FAs. The mechanistic details of fatty acid uptake into cells remains poorly understood. Here, the authors identify CD36 internalization via cavaeolae and demonstrate dynamic palmitoylationof CD36 is required for endocytic uptake of fatty acids.

Although two-dimensional (2D) layered double hydroxides (LDHs) have been widely used as efficient nanoagents for biological diagnosis and treatment, they have been found to be inert as photosensitizers (PSs) for photodynamic therapy (PDT). Herein, we report the defect engineering of ultrathin 2D CoMo-LDH and NiMo-LDH nanosheets as highly active inorganic PSs for PDT in the third near-infrared (NIR-III) window. Hydrothermal-synthesized 2D CoMo-LDH and NiMo-LDH nanosheets are etched via a simple acid treatment to obtain defect-rich CoMo-LDH and NiMo-LDH nanosheets. Importantly, the defect-rich CoMo-LDH nanosheets exhibit much higher activity (~97 times) for generation of reactive oxygen species than that of the pristine CoMo-LDH nanosheets under a NIR-III 1567 nm laser irradiation. Therefore, after modification with polyethylene glycol, the defect-rich CoMo-LDH nanosheets can be used as an efficient inorganic PS for PDT to efficiently induce cancer cells apoptosis in vitro and eradicate tumors in vivo under 1567 nm laser irradiation. Defect engineering of 2 dimensional layered double hydroxide sheets improves their photocatalytic activity. Here, the authors etch sheets in acid and show that the etched sheets generate substantially more reactive oxygen species that untreated sheets and the treated sheets can be used to kill cancer cells in vitro and in vivo.

Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods 1 . Here we applied multiple single-cell and single-nucleus assays (>400,000 nuclei or cells) and spatial imaging technologies to a broad spectrum of healthy reference kidneys (45 donors) and diseased kidneys (48 patients). This has provided a high-resolution cellular atlas of 51 main cell types, which include rare and previously undescribed cell populations. The multi-omic approach provides detailed transcriptomic profiles, regulatory factors and spatial localizations spanning the entire kidney. We also define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive (successful or maladaptive repair), transitioning and degenerative states. Molecular signatures permitted the localization of these states within injury neighbourhoods using spatial transcriptomics, while large-scale 3D imaging analysis (around 1.2 million neighbourhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways that are relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations. A high-resolution kidney cellular atlas of 51 main cell types, including rare and previously undescribed cell populations, represents a comprehensive benchmark of cellular states, neighbourhoods, outcome-associated signatures and publicly available interactive visualizations.

Preventing aggregation of amyloid beta (Aβ) peptides is a promising strategy for the treatment of Alzheimer’s disease (AD), and gold nanoparticles have previously been explored as a potential anti-Aβ therapeutics. Here we design and prepare 3.3 nm L- and D-glutathione stabilized gold nanoparticles (denoted as L3.3 and D3.3, respectively). Both chiral nanoparticles are able to inhibit aggregation of Aβ42 and cross the blood-brain barrier (BBB) following intravenous administration without noticeable toxicity. D3.3 possesses a larger binding affinity to Aβ42 and higher brain biodistribution compared with its enantiomer L3.3, giving rise to stronger inhibition of Aβ42 fibrillation and better rescue of behavioral impairments in AD model mice. This conjugation of a small nanoparticle with chiral recognition moiety provides a potential therapeutic approach for AD. Nanoparticles are being explored as a potential method to target Aβ aggregation in Alzheimer’s disease. Here, the authors develop gold nanoparticles that were capped with chiral L or D-glutathione which has been shown to improve BBB permeability and demonstrate their ability to improve cognitive function in a mouse model of AD.