Acute kidney injury (AKI) suffers from limited therapeutic efficacy largely owing to insufficient targeted accumulation and uncontrollable on-demand delivery of conventional therapeutics. To overcome these drug delivery bottlenecks, we develop an ultrasound-triggered cascade-targeted nanoplatform (LSMND). Different from conventional static nanocarriers with fixed particle sizes, LSMND achieves controllable in situ particle remodeling and deep renal delivery through ultrasound-activated perfluoropentane (PFP) liquid-gas phase transition. Surface-functionalized LTH peptides further endow LSMND with active targeting ability, enabling precise enrichment in injured proximal tubules. The oxidative microenvironment induces the cleavage of ROS-responsive thioketal (TK) linkages, triggering programmed disassembly of LSMND and spatiotemporal co-delivery of SS31 and MCC950. The released SS31 preserves mitochondrial structural integrity and ameliorates mitochondrial bioenergetics, thereby restricting mtDNA leakage and suppressing Z-DNA binding protein 1 (Zbp1)-associated inflammatory activation. MCC950 suppresses the NLRP3 inflammatory cascade, synergistically potentially alleviates the detrimental metabolic-inflammatory loop. Integrated proteotranscriptomic analyses verify that LSMND alleviates upstream mitochondrial stress and blocks aberrant pro-inflammatory activation. In a murine renal ischemia-reperfusion injury model, LSMND substantially alleviates tubular necrosis and promotes renal functional recovery. This US-activated cascade-targeted nanoplatform provides a controllable and precise therapeutic strategy for AKI treatment.
Sepsis, a severe illness marked by immune dysregulation and widespread inflammation, involves macrophage pyroptosis as a key player. This study explores the impact of RNA N6-methyladenosine (m6A) modification and investigates whether fat mass and obesity-associated protein (FTO)-mediated demethylation influences macrophage pyroptosis by modulating NOD-like receptor protein 3 (NLRP3) inflammasome activation. The research aims to unravel the workings of the FTO-m6A-NLRP3 pathway in macrophage pyroptosis and assess the therapeutic potential of targeted intervention using biomimetic nanovesicles. Results:By developing CD11b/CD206 dual-ligand modified macrophage-derived small extracellular vesicle (sEV)-biomimetic nanovesicles loaded with FB23-2, an FTO inhibitor (FB23-2-loaded Dual-Vesicles) and employing various molecular techniques, including MeRIP-qPCR, WB, scRNA-seq, spatial transcriptomics, and metabolomics, the study delves into the mechanism by which FTO-regulated m6A modification impacts NLRP3 inflammasome and inflammatory metabolic pathways. Findings reveal upregulated FTO levels in septic macrophages, reduced m6A modification levels, and increased expression of NLRP3 and interleukin-1 beta (IL-1β). Treatment with an FTO inhibitor increased m6A modification of Il1b mRNA, reduced IL-1β expression, and attenuated NLRP3 inflammasome activation and pyroptosis-associated changes. FB23-2-loaded Dual-Vesicles showed enhanced macrophage uptake and pulmonary enrichment, improved 7-day survival, and reduced inflammatory injury in murine models. Conclusions: These findings support further evaluation of the FTO-m6A-NLRP3-pyroptosis regulatory network as a targeted epigenetic intervention strategy in sepsis and related inflammatory diseases.
Microplastics (MPs) and nanoplastics (NPs) are increasingly detected in environmental matrices and human biological samples, raising concern about their potential effects on cellular function and human health. This structured narrative review critically evaluates evidence from in vitro, in vivo, ex vivo, and human studies, with emphasis on the mechanisms governing particle–cell interactions and the methodological limitations that affect interpretation. Cellular contact, uptake, intracellular trafficking, and delivered dose are influenced by particle size, shape, polymer composition, surface chemistry, environmental aging, aggregation state, and biocorona formation. Experimental studies have recurrently reported lysosomal and mitochondrial dysfunction, oxidative stress, inflammatory signaling, impaired autophagic clearance, genomic instability, metabolic disruption, and barrier dysfunction following MNP exposure. These responses are highly interconnected and may form self-reinforcing stress networks rather than independent pathways. However, their magnitude and biological relevance vary substantially according to particle characteristics, exposure concentration and duration, and experimental model. Human studies demonstrate the presence of plastic-associated material in blood and selected tissues, supporting systemic exposure and possible translocation, but do not by themselves establish intracellular toxicity or causal relationships with specific diseases. Translation of experimental findings is further limited by inconsistent particle characterization, non-equivalent dose metrics, contamination risk, and the frequent use of short-term exposures at concentrations exceeding reported human burdens. Greater mechanistic and translational confidence will require standardized exposure and dosimetry frameworks, chronic low-dose studies, environmentally relevant particles, human-relevant multicellular models, organoids and organ-on-chip platforms, multi-omics integration, and validated imaging and biosensing approaches. Overall, current evidence supports the biological plausibility of MNP-induced cellular injury, but remains insufficient to establish direct causation between MNP exposure and specific human diseases.
Seawater-associated infected wounds involve alkaline and hyperosmotic stress, polymicrobial contamination, biofilms, and persistent inflammation, collectively delaying healing. Herein, we developed QCB-Au@SPG, a pH-responsive hydrogel integrating fluorescent antibacterial QCB-Au, an alkali-sensitive SA-PBA network, and photocrosslinkable GelMA. QCB-Au@SPG exhibited a linear fluorescence response across pH 4–8 (R² = 0.998), enabling semi-quantitative visualization of pH variation, while alkaline conditions moderately enhanced QCB-Au release. The hydrogel reduced the survival rates of S. aureus, E. coli, and V. vulnificus to 0.55
Hydrogen peroxide (H2O2) is an essential molecule for cellular signaling transduction processes in living systems. Therefore, its low-background and in situ imaging in vivo is critical for the diagnosis and functional studies of related diseases. However, most probes for in vivo imaging of H2O2 are often limited by short emission wavelengths, high tissue autofluorescence, and interference from the complex microenvironment. Herein, we have developed a microenvironment-tailored catalytic nanoprobe (LNP@MB-Mo) that enables autofluorescence-free chemiluminescence (CL) imaging of H2O2 in vivo. The nanoprobe is constructed using liposomes as a carrier to co-encapsulate methylene blue (MB), sodium molybdate (Na2MoO4), and sodium carbonate (Na2CO3). By pre-establishing a localized alkaline microenvironment, the nanoprobe promotes the molybdate ions (MoO42−)-mediated catalytic conversion of H2O2 into singlet oxygen (1O2), which subsequently oxidizes MB to produce a near-infrared chemiluminescence (NIR CL) signal. In addition, the selective permeability of the liposomal membrane effectively suppresses interference from reducing biomolecules glutathione (GSH), thereby substantially improving the response stability and reliability in complex biological environments. The nanoprobe showed good responsiveness to H2O2, featuring high selectivity, high sensitivity and rapid response ability. Owing to its autofluorescence-free and high activation contrast, the nanoprobe has been successfully applied to image H2O2 in inflammation models, as well as in subcutaneous or orthotopic hepatocellular carcinoma (HCC) tumor models in mice with a high signal-to-background ratio (SBR). The capability of our nanoprobe for real-time CL imaging of H2O2-associated diseases, highlights its future integration potential for imaging molecular events related to H2O2 or other H2O2 producing enzymes of interests.
