Liver cancer remains a significant global health challenge, with rising incidence rates and limited treatment options, underscoring the urgent need for innovative and effective therapeutic strategies. Sonodynamic therapy (SDT) stands as a promising non-invasive treatment technique, yet its advancement faces challenges due to difficulties in precisely co-localizing the tumor, sonosensitizers, and focused ultrasound (FUS). Additionally, the absence of feasible methods for in vivo detection of reactive oxygen species (ROS) hampers further research and development in this field. Herein, our study introduces a novel sonosensitizer, a phthalocyanine-conjugated mesoporous silicate nanoparticle loaded with allylhydrazine (PAMSN). We confirm that PAMSN not only amplifies the fluorescent signal of phthalocyanine (1.9-fold) but also generates nitrogen gas bubbles via the interaction between allylhydrazine (ALZ) and ROS. This distinct attribute positions PAMSN as a versatile multimodal contrast agent suitable for in vivo tumor imaging and SDT applications. Moreover, we establish a FUS platform that integrates fluorescent and ultrasonic imaging guidance, ensuring the precise delivery of ultrasound to the targeted area. In conjunction with PAMSN, this platform can effectively treat orthotopic liver cancer in a murine model while in vivo monitoring of ROS and detection of cavitation are enabled. In conclusion, PAMSN-mediated SDT with the multimodal imaging-guided SDT platform facilitates a precise and controllable SDT process, providing a promising tool for safer and more effective SDT in clinical tumor treatment.

The development of a robust and biocompatible pH-sensing platform is critical for monitoring intracellular processes and diagnosing diseases. Here, we present a smart ultrastable ratiometric fluorescence nano pH sensor based on silica-coated liposome nanoparticles (cerasome, 138.4 nm). The sensor integrates pH-sensitive dye, pyranine, within cerasome, achieving enhanced photostability, sensitivity, and biocompatibility. Its unique ratiometric design enables precise pH monitoring with minimal photobleaching and quenching, covering a linear detection range of pH 6.25-8.5. The hybrid nanoparticles exhibit high morphological stability, making them suitable for real-time intracellular pH measurement. This novel platform shows great promise for applications in cellular biology, disease diagnosis, and therapeutic monitoring, offering a versatile tool for biomedical research.

Purpose: To assess the anticancer effect of microbubbles (MBs) in combination with sinoporphyrin sodium (DVDMS)-mediated sonodynamic therapy (SDT) for the in vitro and in vivo treatment of hepatocellular carcinoma (HCC). Methods: HepG2 cells were used for in vitro experiments. Reactive oxygen species (ROS) production was detected using 2',7'-dichlorodihydrofluorescein diacetate and singlet oxygen sensor green in vitro and in solution, respectively. Cytotoxicity was evaluated using a Cell Counting Kit 8 assay and the calcein AM/PI double-staining method. Annexin V-FITC/PI staining was employed to analyze the rate of cell apoptosis. Cell surface calreticulin exposure, high mobility group box 1 release, and adenosine triphosphate secretion were measured to detect immunogenic cell death (ICD). The anticancer effect of the combination therapy was further assessed in Hepa1-6 tumor-bearing mice. Results: Compared with SDT alone, ROS production in the MBs + SDT group was enhanced 1.2-fold (p < 0.0001). The cytotoxic effect of DVDMS-mediated SDT on HepG2 cells was concentration-dependent, and the additional application of MBs increased cytotoxicity. Additionally, MBs augmented the SDT-induced apoptosis rate from 33.26 ± 13.48 to 72.95 ± 7.95% (p < 0.01). Notably, our results demonstrated that MBs can enhance SDT-induced ICD. In in vivo experiments, SDT combined with MBs significantly reduced tumor volume, with negligible differences in mouse body weight. Furthermore, MBs effectively enhanced SDT-induced tumor tissue destruction. Conclusion: The present study indicates that MBs can markedly improve the anticancer effects of SDT in HCC.

To improve the selective separation performance of silica nanofibers (SiO2 NFs) for cesium ions (Cs+) and overcome the defects of Prussian blue nanoparticles (PB NPs), PB/SiO2-NH2 NFs were prepared to remove Cs+ from water. Among them, 3-aminopropyltriethoxysilane (APTES) underwent an alkylation reaction with SiO2, resulting in the formation of a dense Si-O-Si network structure that decorated the surface of SiO2 NFs. Meanwhile, the amino functional groups in APTES combined with Fe3+ and then reacted with Fe2+ to form PB NPs, which anchored firmly on the aminoated SiO2 NFs surface. In our experiment, the maximum adsorption capacity of PB/SiO2-NH2 NFs was 111.38 mg/g, which was 31.5 mg/g higher than that of SiO2 NFs. At the same time, after the fifth cycle, the removal rate of Cs+ by PB/SiO2-NH2 NFs adsorbent was 75.36% ± 3.69%. In addition, the adsorption isotherms and adsorption kinetics of PB/SiO2-NH2 NFs were combined with the Freundlich model and the quasi-two-stage fitting model, respectively. Further mechanism analysis showed that the bond between PB/SiO2-NH2 NFs and Cs+ was mainly a synergistic action of ion exchange, electrostatic adsorption and membrane separation.

Pancreatic ductal adenocarcinoma (PDAC) poses a challenge in oncology due to its high lethality and resistance to immunotherapy. Recently, emerging research on the stimulator of interferon gene (STING) pathway offers novel opportunities for immunotherapy. Although STING expression is retained in PDAC cells, the response of PDAC cells to STING agonists remains ineffective. Signal transducer and activator of transcription 3 (STAT3), a downstream pathway of STING, is notably overexpressed in pancreatic cancer and related to tumor survival and immune escape. We observed that inhibiting STAT3 signaling post-STING activation effectively suppressed tumor growth through signal transducer and activator of transcription 1 (STAT1)-mediated apoptosis but led to a potential risk of immune-related adverse events (irAEs). To address this issue, we designed a tumor-penetrating liposome for the codelivery of STING agonist and STAT3 inhibitor. These nanoparticles regulated the STING/STAT3 signaling axis and effectively inhibited the proliferation and survival of tumor. Simultaneously, we found a significant increase in the activation of NK cells and CD8+ T cells after treatment, leading to robust innate immunity and adaptive immune response. We highlight the potential of regulating the STING/STAT3 axis as a promising treatment for improving clinical outcomes in PDAC patients.

Toll-like receptors (TLRs), found on antigen-presenting cells including macrophages and dendritic cells, are essential for identifying infections and initiating adaptive immunity. Therefore, among the many strategies for cancer immunotherapy, methods based on TLR agonists have been one of the most pursued directions. In addition to these immunologic activation functions, TLR agonists also contribute to reshaping immunosuppressive "cold" tumors into "hot" tumors. Despite their remarkable immunomodulatory properties, TLR agonists exhibit a low therapeutic index. Non-specific stimulation of various immune cells may produce excessive levels of inflammatory cytokines, leading to systemic side effects. The continuous development in nanotechnology has presented the possibility of innovative therapies to improve the efficacy and safety of TLR agonist-based immunotherapy. In this review, we describe the functions of TLRs in the tumor microenvironment, as well as, the pathways that activate immune responses, in addition to summarizing and discussing recent developments in nanotechnology for immunomodulation with TLR agonists, including platforms such as nanocapsules, micelles, liposomes, nanogels, and others. Nanotechnology can effectively improve the efficacy of TLR agonist-based immunotherapy, while playing a pivotal role in solving the limitations of the current treatment.

荧光分子成像具有灵敏度高、成像时间短、无放射性损伤、价格较低等优势,广泛应用于药物的开发递送和疾病的临床检测.荧光分子成像需要用到荧光探针,包括内源性荧光基团(例如色氨酸、血红蛋白)、基因表达的荧光蛋白(例如绿色荧光蛋白)、外源性小分子荧光基团和荧光纳米颗粒(例如吲哚菁绿、量子点)等.其中外源性荧光探针是目前研究的热点,它们可以与生物大分子或药物结合,对其生物学行为进行成像监测;还可以通过化学修饰的方法连接靶向配体,实现对目标组织的靶向荧光成像,提高对肿瘤的诊断能力.

Conventional NO gas generation based on l-arginine (l-Arg) is usually dependent on H2O2 and O2, both of which are very limited within the tumor microenvironment, thus greatly limiting l-Arg's therapeutic effect. Herein, a novel nanoplatform for efficiently triggering NO production based on ultrasound-induced piezocatalysis was developed, which was fabricated by coating amphiphilic poly-l-arginine (DSPE-PEG2000-Arg, DPA) on the piezoelectric material of barium titanate (BTO). The resulting BTO@DPA nanoparticles can efficiently generate H2O2, 1O2, and O2 via ultrasound-induced piezocatalysis based on BTO and oxidize the surface arginine to produce NO, which can even further interact with the reactive oxygen species (ROS) to produce more reactive peroxynitrite, thus inducing serious tumor cell apoptosis both in hypoxia and normoxia. After intravenous injection, BTO@DPA accumulated well at the tumor tissue at 4 h postinjection; later, ultrasound irradiation on the tumor not only achieved the best tumor inhibition rate of ∼70% but also completely inhibited tumor metastasis to the lungs via the alleviation of tumor hypoxia. Such a strategy was not dependent on the tumor microenvironment and can be well controlled by ultrasound irradiation, providing a simple and efficient therapy paradigm for hypoxic tumor.

Clinically used small-molecular photosensitizers (PSs) for photodynamic therapy (PDT) share similar disadvantages, such as the lack of selectivity towards cancer cells, short blood circulation time, life-threatening phototoxicity, and low physiological solubility. To overcome such limitations, the present study capitalizes on the synthesis of ultra-small hydrophilic porphyrin-based silica nanoparticles (core-shell porphyrin-silica dots; PSDs) to enhance the treatment outcomes of cancer via PDT. These ultra-small PSDs, with a hydrodynamic diameter less than 7 nm, have an excellent aqueous solubility in water (porphyrin; TPPS3-NH2) and enhanced tumor accumulation therefore exhibiting enhanced fluorescence imaging-guided PDT in breast cancer cells. Besides ultra-small size, such PSDs also displayed an excellent biocompatibility and negligible dark cytotoxicity in vitro. Moreover, PSDs were also found to be stable in other physiological solutions as a function of time. The fluorescence imaging of porphyrin revealed a prolonged residence time of PSDs in tumor regions, reduced accumulation in vital organs, and rapid renal clearance upon intravenous injection. The in vivo study further revealed reduced tumor growth in 4T1 tumor-bearing bulb mice after laser irradiation explaining the excellent photodynamic therapeutic efficacy of ultra-small PSDs. Thus, ultrasmall hydrophilic PSDs combined with excellent imaging-guided therapeutic abilities and renal clearance behavior represent a promising platform for cancer imaging and therapy.

Targeted photodynamic therapy (TPDT) based on the photosensitizers responsive for tumor microenvironment is promising because of the better anti-tumor effect and less phototoxicity against normal tissue than the traditional PDT. Nanoparticle-based stimuli-responsive photosensitizers have been widely explored for TPDT. Based on the acidic microenvironments in solid tumors, an ultrasmall pH-responsive silicon phthalocyanine nanomicelle (PSN) (smaller than 10[Formula: see text]nm) was designed for selective PDT of tumor. PSN had high drug loading efficacy (more than 28%) and exhibited morphological transitions, enhanced fluorescence and improved singlet oxygen yield under acidic environments. PSN was renal clearable and could rapidly accumulate and be retained at tumor sites, achieving a tumor-inhibiting effect better than phthalocyanine micelle without pH response. Tumors of mice treated with PSN for PDT were completely ablated without recurrence. Thus, we have developed a phthalocyanine-based pH-responsive micelle with excellent tumor targeting ability, which is expected to realize the selective PDT of tumor.

Atherosclerosis is an important pathological basis of several cardiovascular diseases and viewed as a fundamental indicator for cardiovascular disease management. Gene therapy is expected to be a very promising approach to treat atherosclerosis. The past few years have seen the approval of several non-viral nucleic acid therapeutics by US Food and Drug Administration (FDA), including Inclisiran, a lipid-lowering RNA drug for atherosclerosis. Compared with viral gene vectors, non-viral nucleic acid therapeutics, especially the RNA therapeutics, is advantageous in several aspects, including low immunogenicity, almost no unwanted genomic integration, high payload size, facile in upscaling manufacturing, etc. Here, we reviewed recent advances in targeted non-viral nucleic acid delivery for gene therapy of atherosclerosis. We first described the hepatocyte-targeted nucleic acid delivery platform technologies for lipid-lowering atherosclerotic therapy. Then we summarized the advances of nucleic acid delivery targeting cells located in the atherosclerotic plaque, including endothelial cells, monocytes, macrophages and vascular smooth muscular cells. This review provides a comprehensive view and roadmap for general readers working in this field.

The pollution of cesium ions (Cs+) in radioactive wastewater has attracted an increasing attention, it is important to develop new materials for highly efficient removal of Cs+. In this study, Prussian blue/biomass activated carbon composites (PB/AC) were prepared by an cost-effective and facile strategy through controllable growth of Prussian blue nanoparticles (PB NPs) on the surface of soybean pods as a precursor of carbon matrix, and its physicochemical properties and Cs+ removal performance compared with that of PB NPs grown on the surface of commercial activated carbon (PB/CAC). The results exhibited that PB NPs were uniformly dispersed on the surface of porous biochar. It was worth noting that PB NPs grafting towards porous biochar could avoid PB NPs aggregation, and thus enhanced the adsorption capacity of porous biochar to Cs+. The maximum adsorption amount of PB/AC reached up to 207.20 mg/g. In comparison with the PB/CAC, the adsorption amounts of PB/AC were elevated by 53.10 mg/g. Meanwhile, PB/AC also demonstrated significant high activity in a broad pH range from 4.0 to 10.0. Moreover, they still have high selectivity toward Cs+ in the presence of competing ions like K+, Na+, Ca2+ and Mg2+. In addition, the kinetic adsorption experiment showed that PB/AC reached adsorption equilibrium within 30 min. After three cycles of regeneration, PB/AC could maintain 99.01% of the original adsorption capacity. Besides, the MTT test and hematoxylin and eosin (H & E) staining showed that PB NPs had good biosafety, and the cell survival rate of HUVECs was still higher than 83.23 +/- 6.41% after exposure for 24 h culture with high concentration of PB NPs (0.50 mg/mL). In brief, the low-cost and highly efficient PB/AC showed great removal efficiencies to Cs+ in radioactive water.

Microbubbles have been the earliest and most widely used ultrasound contrast agents by virtue of their unique features: such as non-toxicity, intravenous injectability, ability to cross the pulmonary capillary bed, and significant enhancement of echo signals for the duration of the examination, resulting in essential preclinical and clinical applications. The use of microbubbles functionalized with targeting ligands to bind to specific targets in the bloodstream has further enabled ultrasound molecular imaging. Nevertheless, it is very challenging to utilize targeted microbubbles for molecular imaging of extravascular targets due to their size. A series of acoustic nanomaterials have been developed for breaking free from this constraint. Especially, biogenic gas vesicles, gas-filled protein nanostructures from microorganisms, were engineered as the first biomolecular ultrasound contrast agents, opening the door for more direct visualization of cellular and molecular function by ultrasound imaging. The ordered protein shell structure and unique gas filling mechanism of biogenic gas vesicles endow them with excellent stability and attractive acoustic responses. What’s more, their genetic encodability enables them to act as acoustic reporter genes. This article reviews the upgrading progresses of ultrasound contrast agents from microbubbles to biogenic gas vesicles, and the opportunities and challenges for the commercial and clinical translation of the nascent field of biomolecular ultrasound.

At present, clinical diagnosis of breast cancer is based on the combination of pathological typesand molecular typing (immunohistochemistry). Yet, it is invasive and unable to show the relationship between keybiological molecules and clinical key information in situ and in real time. This paper introduces the latest researchprogress of molecular classification of breast cancer using molecular imaging technology. Fluorescence imaginghas high sensitivity and does not rely too much on image analysis. Thus, molecular classification information ofbreast cancer can be obtained in real time and multi-channel, quantitatively or semi quantitatively by using the cor‐responding fluorescent probes. Therefore, the development of safe and efficient near-infrared fluorescent molecu‐lar probes with strong tissue penetration is the focus of future fluorescence imaging technology and molecular clas‐sification of breast cancer

Cyanine is a meritorious fluorogenic core for the construction of fluorescent probes and its phototherapeutic potential has been enthusiastically explored as well. Alternatively, the covalent conjugation of cyanine with other potent therapeutic agents not only boosts its therapeutic efficacy but also broadens its therapeutic modality. Herein, we summarize miscellaneous cyanine–therapeutic agent conjugates in cancer theranostics from literature published between 2014 and 2020. The application scenarios of such theranostic cyanine conjugates covered common cancer therapeutic modalities, including chemotherapy, phototherapy and targeted therapy. Besides, cyanine conjugates that serve as nanocarriers for drug delivery are introduced as well. In an additional section, we analyze the potential of these conjugates for clinical translation. Overall, this review is aimed to stimulate research interest in exploring unattempted therapeutic agents and novel conjugation strategies and hopefully, accelerate clinical translation in this field.

Cyanine is a class of fluorescent dye with meritorious fluorescence properties and has motivated numerous researchers to explore its imaging capabilities by miscellaneous structural modification and functionalization strategies. The covalent conjugation with other functional molecules represents a distinctive design strategy and has shown immense potential in both basic and clinical research. This review article summarizes recent achievements in cyanine conjugate-based probes for biomedical imaging. Particular attention is paid to the conjugation with targeting warheads and other contrast agents for targeted fluorescence imaging and multimodal imaging, respectively. Additionally, their clinical potential in cancer diagnostics is highlighted and some concurrent impediments for clinical translation are discussed.

Stage IV breast cancer, which has a high risk of invasion, often develops into metastases in distant organs, especially in the lung, and this could threaten the lives of women. Thus, the development of more advanced therapeutics that can efficiently target metastatic foci is crucial. In this study, we built an dual-acting therapeutic strategy using micelles with high stability functionalized with fibronectin-targeting CREKA peptides encapsulating two slightly soluble chemotherapy agents in water, doxorubicin (D) and vinorelbine (V), which we termed C-DVM. We found that small C-DVM micelles could efficiently codeliver drugs into 4T1 cells and disrupt microtubule structures. C-DVM also exhibited a powerful ability to eradicate and inhibit invasion of 4T1 cells. Moreover, an in vivo pharmacokinetics study showed that C-DVM increased the drug circulation half-life and led to increased enrichment of drugs in lung metastatic foci after 24 h. Moreover, dual-acting C-DVM treatment led to 90% inhibition of metastatic foci development and reduced invasion of metastases. C-DVM could potentially be used as a targeted treatment for metastasis and represents a new approach with higher therapeutic efficacy than conventional chemotherapy for stage IV breast cancer that could be used in the future.

The recent progress in the development of highly biocompatible nanoplatforms mostly encompasses the use of biological excipients such as red blood cells, cancer cell membranes, and also platelets. Such specialized vectors, if mimicked correctly, have intrinsic ability to navigate through the biological system and perform their intended action without eliciting any cascade of inflammatory processes. Naturally, platelets have been found to accumulate in the wound sites and also interact with circulating tumor cells (CTCs). Inspired by the targeting ability of platelets and the clinical success of ultrasound, herein we developed a novel ultrasound contrast agent (UCA) by backfilling of an insoluble gas into the platelets after lyophilization ex vivo. The as-prepared platelet-based ultrasound contrast agent (P-UCA) disguised the structural integrity of the natural platelets with an average diameter of 3.1 +/- 0.4 mu m, and could enhance the ultrasound signal both in vitro and in vivo. Besides, we further evaluated that such platelet particles could facilitate active loading of ICG molecules for prolonged in vivo fluorescence imaging compared to the free ICG. Taking all the results together, we established that biological structures such as platelets could be repurposed ex vivo as a"shell" to encapsulate gas and be further extended to load ICG for real-time ultrasound and fluorescence imaging respectively. This not only indicates many potential uses of these MBs in the diagnosis of platelet-related diseases, such as vascular damage, thrombosis, and atherosclerosis, but also serves as a powerful platform with multimodal theranostic capability after active loading of a variety of therapeutic and diagnostic agents.

Chemotherapy suffers from some limitations such as poor bioavailability, rapid clearance from blood, poor cellular uptake, low tumor accumulation, severe side effects on healthy tissues and most importantly multidrug resistance (MDR) in cancer cells. Nowadays, a series of smart drug delivery system (DDS) based on amphiphilic drug conjugates (ADCs) has been developed to solve these issues, including polymer-drug conjugate (PDC), phospholipid-mimicking prodrugs, peptide-drug conjugates (PepDCs), pure nanodrug (PND), amphiphilic drug-drug conjugate (ADDC), and Janus drug-drug conjugate (JDDC). These ADCs can self-assemble into nanoparticles (NPs) or microbubbles (MBs) for targeted drug delivery by minimizing the net amount of excipients, realizing great goals, such as stealth behavior and physical integrity, high drug loading content, no premature leakage, long blood circulation time, fixed drug combination, and controlled drug-release kinetics. Besides, these self-assembled systems can be further used to load additional therapeutic agents and imaging contrast agents for combined therapy, personalized monitoring of in vivo tumor targeting, and the pharmacokinetics of drugs for predicting the therapeutic outcome. In this review, we will summarize the latest progress in the development of ADCs based combination chemotherapy and discuss the important roles for overcoming the tumor MDR.

Liposomes are a type of biomimetic nanoparticles generated from self-assembling concentric lipid bilayer enclosing an aqueous core domain. They have been attractive nano-carriers for the delivery of many drugs (e.g. radiopharmaceuticals, chemotherapeutic agents, porphyrin) and diagnostic agents (e.g. fluorescent dyes, quantum dots, Gadolinium complex and Fe3O4) by encapsulating (or adsorbing) hydrophilic one inside the liposomal aqueous core domain (or on the bilayer membrane surface), and by entrapping hydrophobic one within the liposomal bilayer. Additionally, the liposome surface can be easily conjugated with targeting molecules. Liposomes may accumulate in cancerous tissues not only passively via enhanced permeability and retention (EPR) effect, but also actively by targeting cancer cell or angiogenic marker specifically. The multimodality imaging functionalization of liposomal therapeutic agents makes them highly attractive for individualized monitoring of the in vivo cancer targeting and pharmacokinetics of liposomes loading therapeutic drugs, and predicting therapeutic efficacy in combination with the helpful information from each imaging technique. The present review article will highlight some main advances of cancer theranostic liposomes with a view to activate further research in the nanomedicine community.