In this study, liposomes loaded with the reactive oxygen species-responsive probe QM-CF (Lipo@QM-CF) were prepared using a phospholipid composition consisting of dipalmitoylphosphatidylcholine (DPPC), sphingomyelin (SM), cholesterol (CHO), DSPE-PEG2000, and DSPE-PEG2000-maleimide, selected for their roles in membrane stability, fluidity, and potential for functional modification. The particle size, stability, encapsulation efficiency, and probe loading status of the liposomes were preliminarily investigated. The results showed that the prepared liposomes exhibited uniform particle size (approximately 160–170 nm, PdI < 0.15) and showed no significant changes in particle size during 21 days of storage at 4°C, indicating good in vitro stability. Elemental analysis revealed that chlorine signals colocalized with the liposome positions, suggesting the colocalization of QM-CF with liposomes. Chemiluminescence imaging further verified the probe loading status: free QM-CF exhibited luminescence only in methanol, while Lipo@QM-CF showed no luminescence but recovered upon methanol demulsification, with further enhancement in the presence of reactive oxygen species, confirming that QM- CF was successfully encapsulated within liposomes and possessed good ROS-responsive release capability. This study successfully demonstrates the construction of a liposome-based probe for ROS imaging, offering a novel strategy for detecting inflammatory microenvironments.

Precise management of the inflammatory response after myocardial infarction necessitates targeted engagement of cellular drivers. Here, we report a pathophysiology-guided theranostic platform that exploits two defining features of pro-inflammatory macrophages, their high-output nitric oxide (NO) production and localized acidic microenvironment, to enable concurrent sensing, quantification, and modulation of post-infarction inflammation. The platform, PM720@NRP, is engineered from platelet membranes encapsulating an NO-responsive NIR-II fluorophore and the immunomodulator FTY720. It delivers three integrated functions: (i) specific, NO-activated NIR-II imaging of inflammatory foci; (ii) machine learning-powered translation of imaging signals into quantitative maps of pro-inflammatory macrophage activity; (iii) acid-triggered release of FTY720 to reprogram macrophages toward a reparative phenotype, synergizing with platelet-derived factors to stimulate angiogenesis. This strategy provided real-time visualization and non-invasive quantification of inflammation, while improving cardiac function and repair. By repurposing pathological biomarkers as intrinsic triggers for diagnosis and treatment, this work establishes a closed-loop, biology-inspired paradigm that autonomously adapts to dynamic disease activity.

Sepsis-associated encephalopathy (SAE) is a life-threatening neuroinflammatory complication of sepsis for which effective treatment remains unavailable. A major challenge is that most therapeutics cannot efficiently cross the blood-brain barrier or simultaneously address the coupled pathological processes driving disease progression, namely microglial pyroptosis and impaired neurotrophic support. Here, we report an ultrasound-gated nanobubble platform designed for SAE that enables sequential pyroptosis blockade and mechanotransduction-mediated neurorepair. The platform consists of sphingosine-1-phosphate-functionalized, disulfiram-loaded nanobubbles (S1P@DSF-NBs), which actively accumulate in inflamed cerebral vasculature via the S1P-S1PR1 axis and serve as a localized reservoir for ultrasound-programmed intervention. Under a dual-ultrasound regimen, low-intensity pulsed ultrasound first induces stable nanobubble oscillation, mechanically activating Piezo1-dependent CREB-BDNF signaling in microglia to restore neurotrophic support. Subsequent high-intensity pulsed ultrasound triggers nanobubble destabilization and localized disulfiram release, leading to gasdermin D inhibition, suppression of pyroptosis, and attenuation of inflammatory amplification. In a murine SAE model, ultrasound-programmed S1P@DSF-NBs reduced systemic and hippocampal inflammation, decreased neuronal loss by 40 %, and improved cognitive performance by 2.24-fold, while reprogramming microglia toward a neuroprotective phenotype and disrupting the pyroptotic inflammatory cascade. These findings demonstrate that ultrasound-programmed nanobubble therapy can concurrently interrupt inflammatory injury and restore neuroprotective signaling in SAE. This work establishes an actively targeted, ultrasound-responsive biomaterials strategy for ultrasound-programmed intervention in SAE and offers a versatile framework for the treatment of other neuroinflammatory disorders.

Although near-infrared II (NIR-II) fluorescence imaging (FI) for accurate and noninvasive diagnosis of solid cancer has been developed as one of the crucial methods for formulating appropriate clinical treatment strategies, it is still hindered by the limited availability of NIR-II nanoprobes. In this study, we aim to develop high performance and biocompatible NIR-II probes based on novel mechanism of the aggregation of NIR fluorephores. Using domain effect of liposomal nanostructures, the J-aggregated state of indocyanine (ICG) NIR-II nanoprobes were elaborately fabricated. Combined with molecular dynamics simulation, the molecular mechanism of the formation of J-aggregated state of ICG molecules was discovered. Results show that the engineered J-aggregated state of ICG with a concentration below 50 mu g/mL can fine tune ICG interactions instead of ICG-intermolecular interactions within liposomal structure. The rational designed ICG cationic liposomes (IJA-CLPs) show 3-fold enhancement in NIR-II intensity compared to the conventional ICG liposomes (ICG-CLPs). Furthermore, for a mouse model of mammary tumors with lymph node metastasis, IF7 peptide-modified IJA-CLPs (IF7-IJA-CLPs) can successfully discriminate tumor cell-metastasized lymph nodes with more than 4-fold fluorescence signal improvement. Thus, it is expected to provide a new avenue for designing NIR-II fluorescent probes for enriching the clinical NIR imaging applications.

Microbubbles have emerged as versatile theranostic platforms in biomedicine. In addition to being used as ultrasound contrast agents, capitalizing on cavitation-mediated physical effects, microbubbles now enable targeted drug delivery and precision tumor ablation. In this study, we engineer doxorubicin (DOX)-loaded multi-interfacial microbubbles (DOX-MIMBs) through interfacial self-assembly of hydrophobic mesoporous silica nanoparticles (hMSNs), establishing a hierarchically structured MIMBs with the sustained acoustic activity. Strong affinity between hMSNs and the gas-liquid interface facilitates cavitation effect transmission. Under low intensity ultrasound (<3 W/cm2) irradiation, primary MIMBs collapse generates secondary daughter bubbles that rapidly stabilize via hMSNs-mediated gas-liquid interface reconstruction and are able to cavitate again. This process enables energy-cascaded cavitation-successive bubble generations persisting until acoustic energy dissipation, achieving prolonged cavitation duration versus conventional lipid-shelled microbubbles. The sequential acoustomechanical perturbation generated by DOX-MIMBs induced synergistic tumor therapy: selective vascular destruction for mechanically collapsed immature tumor vasculature and enhanced chemotherapy for wider distribution and deeper penetration of DOX in tumors. Utilizing sequential bubble cavitation-induced shockwave and microstreaming, by integrating tumor vasculature mechanical disruption and deep tumor DOX penetration chemotherapy, DOX-MIMBs achieved tumor volume appropriate 90 % reduction in renal cell carcinoma models. Such elaborated DOX-MIMBs mechano-pharmaceutical delivery system achieve a paradigm shift from systemic drug bombardment to local mechanochemical tumor suppression and provide a powerful strategy for tumor precision therapy.

Dynamic pathology-adaptive nanodelivery systems represent a promising frontier in acute ischemic stroke (AIS) therapy. Here, we report a thrombo-inflammatory cascade-targeted biomimetic nanobubble engineered through gas-liquid interfacial modular assembly of platelet membranes and immunomodulator fingolimod (FTY720). Molecular dynamics simulations uncovered a gas-liquid interfacial self-organization mechanism driving the ordered spatial distribution of platelet membrane lipid rafts and amphiphilic FTY720 to fabricate platelet membrane coated FTY720 nanobubble (PFNB). Such modular assembled PFNBs can promote the effective presentation of targeted proteins and drug molecular functions on the biointerface, enabling precise sequential lesion targeting, enhanced blood-brain barrier penetration and inflammatory microglial uptake, significantly improving drug delivery efficiency. Therapeutic efficacy analysis via whole-genome RNA sequencing demonstrated a virtuous cycle between anti-inflammatory regulation and vascular protection, ultimately mitigating the brain tissue damage. Therefore, PFNBs provide a paradigm for the modular construction and biointerface efficacy regulation of multifunctional integrated biomimetic nano-delivery systems, offering promising strategies for multi-target synergistic treatment of AIS.

Long regarded as a toxic substance, hydrogen sulfide (H2S) is now recognized as an essential gaseous signaling molecule that demonstrates dual modulation capacities in biological regulation and disease progression. Contemporary research delineates the dynamic enzymatic production pathways (mediated by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST)) alongside spatially organized signaling networks that govern its systemic influence on neuronal integrity, cardiovascular adaptation, and energy metabolism. Within the 10-100 μM range, this gaseous mediator exerts tissue-protective functions through vascular relaxation, suppression of inflammation, and inhibition of cell death. Conversely, imbalanced H2S levels-whether insufficient or excessive-correlate with pathological cascades involving neoplastic transformation, synaptic degeneration, and redox imbalance. This analysis systematically examines progress in precision-controlled H2S modulation technologies, particularly stimuli-responsive delivery architectures designed to resolve its concentration-dependent paradoxes. Emerging nanoscale delivery systems demonstrate enhanced spatiotemporal resolution in capitalizing on H2S's dichotomous bioactivities for managing cerebrovascular pathologies, malignant proliferation, and mitochondrial dysfunction. Current challenges and opportunities are further discussed regarding therapeutic window optimization and biosafety profiling, proposing convergent approaches that integrate material science with systems biology to actualize H2S's clinical potential.

Abstract Although treatments for myocardial infarction have advanced significantly, the global mortality due to ischemia and subsequent reperfusion injury remains high. Here, a platelet (PLT) membrane nanocarrier (PL720) that encapsulates L‐arginine and FTY720 to facilitate the cascade‐targeted delivery of these substances to the myocardial injury site and enable the controlled release of L‐arginine and FTY720 is developed. Such an innovative approach shows enhanced cardioprotection through multiple target strategies involved in ischemia–reperfusion injury and late reperfusion inflammation. During the ischemia–reperfusion phase, PL720 targets and accumulates in damaged coronary arteries. PL720 rapidly releases L‐arginine, stimulating endothelial cells to produce NO, thereby dilating blood vessels and promoting blood flow recovery, while FTY720's sustained release exerts anti‐apoptotic effects. During the late reperfusion inflammatory phase, PL720 is captured by circulating inflammatory monocytes and transported into a deeper ischemic myocardial lesion. PL720 promotes macrophage polarization and accelerates the inflammatory repair. Furthermore, the issue of bradycardia associated with the clinical use of FTY720 is innovatively relieved. Therefore, PL720 is a vascular injury and inflammation dual targeting strategy, exhibiting significant potential for multi‐targeted therapy and clinical translation for cardiac injury.

Thrombolytic therapy is one of the most effective treatments for thrombus dissolution and recanalization of blocked vessels in thrombotic diseases. However, the application of the thrombolytic strategy has been limited due to unsatisfactory thrombolytic efficacy, relatively higher bleeding complications, and consequently restricted indications. Recombinant staphylokinase (r-SAK) is a third-generation thrombolytic agent produced by genetic engineering technology, which exhibits a better thrombolytic efficacy than urokinase and recombinant streptokinase. Inspired by the natural affinity of platelets in hemostasis and pathological thrombosis, we developed a platelet membrane (PM)-coated r-SAK (PM-r-SAK). Results from animal experiments and human in vitro studies showed that the PM-r-SAK had a thrombolytic efficacy equal to or better than its 4-fold dose of r-SAK. In a totally occluded rabbit femoral artery thrombosis model, the PM-r-SAK significantly shortened the initial recanalization time compared to the same dose and 4-fold dose of r-SAK. Regarding the recanalized vessels, the PM-r-SAK prolonged the time of reperfusion compared to the same dose and 4-fold dose of r-SAK, though the differences were not significant. An in vitro thrombolytic experiment demonstrated that the thrombolytic efficacy of PM-r-SAK could be inhibited by platelet-poor plasma from patients taking aspirin and ticagrelor. PM coating significantly improves the thrombolytic efficacy of r-SAK, which is related to the thrombus-targeting activity of the PM-r-SAK and can be inhibited by aspirin- and ticagrelor-treated plasma.

Effective, precise, and controllable oxygen delivery is crucial for regulating the oxygenation balance of brain tissue at the early stages of acute ischemic stroke (AIS) because the absence of oxygen may result in a series of highly interconnected vascular-neural pathological events, including oxidative stress, inflammation, and neuroapoptosis. In this study, platelet membrane-reassembled oxygen nanobubbles (PONBs) were constructed for oxygen delivery to protect AIS. Benefiting from the preserved natural targeting ability of platelet membranes, oxygen can be controlled release into the hypoxia lesion at the preperfusion stage due to vascular injury targeting and oxygen sustained diffusion capability after PONBs administration. Furthermore, synergizing with bioactive components carried by platelet membranes, PONBs can inhibit post-AIS vascular occlusion and maintain blood-brain barrier integrity, thereby facilitating enhanced oxygen delivery of PONBs, establishing a positive feedback loop between oxygen delivery and AIS protection. Additionally, the accumulation of PONBs enhances the ultrasound imaging contrast, enabling precise localization and dynamic monitoring of AIS lesions. Thus, PONBs represent a promising strategy for the diagnosis and treatment of AIS.

Sulfur-substituted dicyanomethylene-4H-chromene (DCM) derivatives based on the intramolecular charge transfer (ICT) mechanism were designed as near-infrared (NIR) fluorescent dyes. Using the Knoevenagel condensation method, the S-DCM-OH(835) fluorescence dye was synthesized, which had an emission wavelength exceeding 800 nm and 220 nm of a Stokes shift. Compared to commercial ICG, S-DCM-OH(835) was not only synchronized in emission wavelength but also far superior in Stokes shifts. These advantages made the design of S-DCM-NIR(835) based on this dye potentially valuable for biological applications. Based on this chemical structure, a fluorescent S-DCM-NIR(835) nanoprobe with a mean diameter of 17.69 nm was fabricated as the NIR imaging nanoprobe. Results showed that the nanoprobe maintained the high-specificity identification of cysteine (Cys) via the Michael addition reaction, with the detection limitation of 0.11 mu M endogenous Cys. More importantly, in an ischemic stroke mouse model, the S-DCM-NIR(835) nanoprobe could monitor the Cys concentration change at stroke lesion due to the disruption of Cys metabolism under the ischemic stroke condition. Such a S-DCM-NIR(835) nanoprobe could not only differentiate the severity of the ischemic stroke using response time but also quantify the concentration of Cys in real-time in vivo.

Objective: The objective of this work is to design and fabricate a novel multifunctional nanocarrier combining thrombus-targeted imaging and ultrasound-mediated drug delivery for the theranostics of thrombotic diseases. Impact Statement: This study develops a new technology that can accurately visualize the thrombus and deliver drugs with controllable properties to diagnose and treat thrombotic diseases. Introduction: Thrombotic diseases are a serious threat to human life and health. The diagnosis and treatment of thrombotic diseases have always been a challenge. In recent years, nanomedicine has brought new ideas and new methods for the theranostics of thrombotic diseases. However, there are also many problems need to be solved, such as biosafety and stability of nanocarriers, early diagnosis, and timely treatment of thrombotic diseases, difficulty in clinical translation. Methods: The S1P@CD-PLGA-rtPA nanobubbles (NBs) were prepared by integrating sulfur hexafluoride (SF6)-loaded poly (D, L-lactide-co-glycolide) (PLGA) NBs, cyclodextrin (CD), sphingosine-1-phosphate (S1P), and recombinant tissue plasminogen activator (rtPA). Results: S1P@CD-PLGA-rtPA NBs had rapid and excellent thrombosis targeting imaging performance based on the specific interaction of S1P-S1PR1 (sphingosine-1-phosphate receptor 1). Furthermore, S1P@CD-PLGA-rtPA NBs that specifically targeting to the thrombosis regions could also respond to external ultrasound to achieve accurate and efficient delivery of rtPA to enhance the thrombolysis effectiveness and efficiency. Conclusion: This study proposes a new idea and strategy of targeting thrombus in rats via the specific interaction of S1P-S1PR1. On this basis, the acoustic response properties of bubble carriers could be fully utilized by combining thrombus-specific targeted imaging and ultrasound-mediated drug delivery for effective thrombolysis, which is expected to be applied in targeted diagnosis and treatment of thrombotic diseases in the future.

Epilepsy is a common neurological disease caused by synchronous firing of hyperexcitable neurons. Currently, patients with epilepsy are typically treated with antiseizure medicines that work by interrupting the hyperexcitability or hypersynchrony of localized neurons or by inhibiting excitatory neurotransmission. However, these drugs do not treat the underlying causes of epilepsy, and nearly one-third of patients have seizures that cannot be controlled by these medications. Animal and clinical evidence suggests that inflammation caused by neuronal and non-neuronal cells within the epilepsy lesion could play a central role in seizure disorders. Here we report a gas-filled nanobubble (NB) conjugated with diammonium glycyrrhizinate (DG) drugs and sphingosine-1-phosphate (S1P) molecules (S1P@DG-NBs) on the lipid shell for targeted therapy and real-time ultrasound visualization applications against neuroinflammatory injury. Affinity of S1P@DG-NBs for the S1P receptor endows these NBs with enhanced targeting capability to the neuroinflammatory microenvironment of epilepsy, where the DG drugs modulate endothelium-microglia-neuron inflammation by inhibiting high-mobility group box 1 molecules and downregulating the Toll-like receptor 4 signaling pathway, resulting in anti-inflammatory M2 microglia that exert anti-epilepsy effects. Our results show that this technology can enhance visualization of epileptic brain and deliver drugs with anti-inflammatory and immunomodulatory properties to ameliorate seizures symptoms.

Globally, the number of deaths caused by various diseases varies according to geographical distribution, gender, and age. Among all types of noncommunicable diseases, cardiovascular diseases such as atherosclerosis, thrombosis, acute myocardial infarction, stroke cause the largest number of deaths, which brings huge health and economic burdens to patients, their families, and the entire society. In clinic, rapid diagnosis and effective therapeutic intervention of cardiovascular diseases are the key to save patients’ lives. However, the conventional diagnosis technology and treatment methods are facing many bottlenecks. There is an urgent need to develop novel theranostic strategies. As a multidisciplinary discipline, the development of nanomaterials and nanostructure-based nanotechnology may provide an alternative and novel direction for the early diagnosis and research of cardiovascular diseases. The application of technologies such as multimodal molecular imaging, ultra-sensitive biosensing, targeted drug delivery, minimally invasive intervention has effectively improved the efficiency of diagnosis and treatment of cardiovascular diseases. This chapter will cover the latest applications and prospects of nanotechnology in the diagnosis and treatment of cardiovascular diseases.

Benefiting from their good biosafety and bioabsorbability, polymeric biodegradable stents (BDSs) have promising application prospects in the treatment of cardiovascular diseases. However, due to the low density of the polymer itself, it is difficult to visualize with medical imaging techniques such as CT and MRI, which leads to difficulties in accurate BDS localization and subsequent non-invasive evaluation. Therefore, modification of BDSs to adapt to monitoring techniques for clinical use without affecting their biocompatibility and mechanical properties is a promising strategy to support the clinical translation of BDSs. In this study, Fe3O4 superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized to modify the BDS by ultrasonic spraying. Due to the T2-weighted MR imaging enhancement capability of SPIONs, the fabricated SPION-BDS can be entirely visualized and long-term monitored under MR imaging. Further, a stent degradation assessment method based on the analysis of image gray value changes was established. In conclusion, the constructed SPION-BDS provides a possible solution for precise localization of BDSs after implantation, and furthermore, opens up opportunities for long-term non-invasive monitoring of in vivo BDS degradation and multimodal imaging assessment of vascular endothelial remodeling.

Vascular inflammation is an early manifestation and common pathophysiological basis of numerous cardiovascular and cerebrovascular diseases. However, effective surveillance methods are lacking. In this study, sulfur hexafluoride (SF6 )-loaded polylactic acid-co-glycolic acid (PLGA) nanobubbles (NBs) with a surface assembly of cyclodextrin (CD) and sphingosine-1-phosphate (S1P) (S1P@CD-PLGA NBs) are designed. The characterization results show that S1P@CD-PLGA NBs with diameters of ≈200 nm have good stability, biosafety, and ultrasound imaging-enhancement effects. When interacting with inflammatory vascular endothelial cells, S1P molecules encapsulated in cyclodextrin cavities exhibit a rapid, excellent, and stable targeting effect owing to their specific interaction with the highly expressed S1P receptor 1 (S1PR1) on the inflammatory vascular endothelial cells. Particularly, the S1P-S1PR1 interaction further activates the downstream signaling pathway of S1PR1 to reduce the expression of tumor necrosis factor-α (TNF-α) to protect endothelial cells. Furthermore, mouse models of carotid endothelial injuries and mesenteric thrombosis demonstrate that S1P@CD-PLGA NBs have excellent capabilities for in vivo targeting imaging. In summary, this study proposes a new strategy of using S1P to target inflammatory vascular endothelial cells while reducing the expression of TNF-α, which has the potential to be utilized in the targeted surveillance and treatment of vascular inflammatory diseases.

大熊猫是中国特有的珍稀物种,西氏贝蛔虫是危害大熊猫最为严重的一种肠道寄生性线虫.针对目前长期药物驱虫导致的大熊猫西氏贝蛔虫耐药及生态污染问题,苏力菌(Bacillus thuringiensis,Bt)晶体蛋白Cry5B因其特异的线虫杀灭活性,是一种理想的新型抗蛔虫病药物候选.本研究拟通过原核表达方式产生BtYBT-1518重组Cry5B蛋白,并评价其对大熊猫西氏贝蛔虫的离体杀灭活性.结果表明,Bt YBT-1518 Cry5B由1 246个氨基酸组成,分子量(MW)为 139.889 kDa,包含 Endotoxin_N、δ-Endotoxin_C、Endotoxin_C、Endotoxin_C2、Cry1Ac_D5结构域,与BtPS86Q3晶体蛋白关系最近.重组Cry5B蛋白在IPTG浓度为1.4mmol/L时表达量最大,表达于菌体上清液.离体杀灭活性实验表明,重组Cry5B蛋白的大熊猫西氏贝蛔虫抑杀效果具有显著的剂量依赖性,对肠道L4期幼虫第3天的ED50值为14.5μg/mL,第7天的ED50值为0.16 μg/mL;但对成虫更敏感,仅作用2 d便可显著下降虫体活性,直至死亡,证实重组Cry5B蛋白对大熊猫蛔虫具有较强的毒杀作用.这些结果为后续论证Bt YBT-1518重组Cry5B蛋白可以作为一种新型、环保的抗大熊猫西氏贝蛔虫病药物提供了数据参考.

Neural stem cells (NSCs) are used to treat various nervous system diseases because of their self-renewal ability and multidirectional differentiation potential. However, an insufficient ability to track their migration in vivo and poor control over their survival and differentiation efficiency are two major critical challenges for clinical application. Here, it is shown that when magnetic nanobubbles (MNBs), which are assembled from magnetic nanoparticles, are internalized by NSCs, intramembrane volumetric oscillation of the MNBs induces an increase in intracellular hydrostatic pressure and cytoskeleton force, resulting in the activation of the Piezo1-Ca2+ mechanosensory channel. This subsequently triggers the BMP2/Smad biochemical signaling pathway, leading to differentiation of NSCs into the neuronal phenotype. Signaling through the Piezo1-Ca2+ -BMP2/Smad pathway can be further accelerated by application of an external shear stress force using low-intensity pulsed ultrasound. More importantly, magnetic resonance imaging and ultrasound imaging surveillance of NSCs based on MNB labeling can be leveraged to provide NSC therapeutic outcomes. Both the in vitro and in vivo findings demonstrate that a bubble nanostructure-induced physical force can modulate and control the mechanical signaling pathway regulating stem cell development.