The rapid emergence of multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) underscores the urgent need for antibiotic-independent antibacterial strategies. Although phototherapy has emerged as a promising alternative, phototherapeutic agents often suffer from poor infection-site specificity, thereby risking collateral damage to healthy tissues and reducing the antibacterial efficacy. Here, we present a biomimetic, stimuli-responsive nanobubble platform, PSP@IR780-PFC(O2), which integrates broad-spectrum bacterial targeting with on-demand phototherapeutic activation triggered by bacterial pore-forming toxins (PFTs). Constructed by co-assembling oxygen-dissolved perfluorocarbon (PFC) with a hybrid membrane of phosphatidylcholine/sphingomyelin (PS) and platelet-derived membrane (PM), and loaded with the photosensitizer IR780, this nanobubble system exhibits robust binding affinity toward both Gram-positive and Gram-negative bacteria via platelet-specific surface adhesins. Moreover, the PS component confers a superior PFT-neutralizing capacity compared to native erythrocyte membranes, thereby enhancing the protection of host cells. Upon PFT-mediated membrane disruption, accelerated oxygen release from the PFC core amplifies local reactive oxygen species (ROS) generation under NIR irradiation, thereby enabling precise, enhanced, spatiotemporally controlled phototherapy. In vivo studies demonstrated effective accumulation at MRSA- and PA-infected sites, significant bacterial eradication, and rapid wound healing. Taken together, PSP@IR780-PFC(O2) offers a generalizable, pathogen-targeted, and toxin-responsive platform for enhanced antibacterial phototherapy, providing a compelling strategy to combat a broad range of bacterial infections without reliance on conventional antibiotics.

Acute kidney injury (AKI) is a severe disease driven by a vicious cycle of tubular damage, oxidative stress, and inflammation, yet current therapies remain limited by poor targeting, short bioavailability, and inability to synergistically regulate multiple pathological pathways. To address this, we develop multifunctional nano-networks (NNWs) through reaction-induced self-assembly of spermidine, epigallocatechin gallate, 2-formylphenylboronic acid, and deferoxamine via dynamic iminoboronate bonds. These NNWs exploit the oxidative AKI microenvironment to trigger disintegration, thereby enabling the site-specific release of therapeutic agents. Deferoxamine and epigallocatechin gallate chelate excess iron to suppress ferroptosis-associated apoptosis, while epigallocatechin gallate and spermidine synergistically mitigate oxidative stress and inflammation through reactive oxygen species scavenging, autophagy promotion, and cytokine inhibition. NNWs overcome the limitations of single-drug therapy or physically combined drug therapy by integrating targeted delivery, controlled release, and multi-pathway modulation, thereby disrupting the self-perpetuating injury cycle. In vitro and in vivo evaluations demonstrated enhanced renal accumulation and superior efficacy in alleviating AKI pathology. This platform provides a promising strategy for spatiotemporally coordinated AKI treatment, offering a blueprint for combinational nanotherapies in complex disease settings.

Antivirulence vaccination represents a promising strategy for infection prevention, but achieving both safety and efficacy in toxoid vaccine preparation remains a challenge. Cell membrane-based nanotoxoids offer a safe delivery platform for bacterial virulence factors in antivirulence vaccination, but limited absorption capacity hampers their efficacy. Here, we develop a lipid-based toxoid vaccine platform, PSV-CNP, comprising a CpG-loaded polymeric core coated with phosphatidylcholine/sphingomyelin (PS) liposomes enriched with bacterial virulence factors. By enhancing virulence factor absorption, PSV-CNP elicits robust humoral immunity. In mice, it provides long-lasting protection against methicillin-resistant Staphylococcus aureus (MRSA) and clinically isolated S. aureus (CI-SA), even under immunosuppression. In Bama pigs, PSV-CNP induces strong immune responses and prevents MRSA and CI-SA invasion. Furthermore, PS-liposomes efficiently absorb virulence factors from Pseudomonas aeruginosa (PA), conferring protection against PA infections. This study establishes PS-coated nanoparticles as a broadly applicable, safe, and effective antivirulence toxoid vaccine platform.

Phototherapy holds great potential for treating cancer and infections but faces limitations related to photosensitizer accumulation, tissue penetration, and diminished photo-conversion efficiency, particularly in deep-seated tumors and infections. Here, a biomimetic phototherapeutic nanodisc platform consisting of erythrocyte membranes and the photosensitizer IR780 is developed. With the advantages of the ultra-small size and exceptional biosafety of cell membrane-derived nanodiscs, this platform facilitates efficient accumulation and deep tissue penetration at disease sites. Upon near-infrared (NIR) irradiation, IR780 delivered via the nanodisc exhibits enhanced photothermal conversion efficiency, markedly inhibiting tumor growth in an orthotopic 4T1 breast cancer model and reducing bacterial load in a methicillin-resistant Staphylococcus aureus (MRSA) skin infection model. Furthermore, the nanodisc platform demonstrates outstanding biocompatibility in mice. In conclusion, this nanodisc system significantly extends the functional potential of cellular nanodiscs, presenting a promising strategy to address the challenges of photosensitizer delivery and biosafety in phototherapeutic applications.

In this investigation, a rapid and reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed for quantification of veliparib in rat plasma and used the method to study the pharmacokinetics and bioavailability of veliparib in rats after oral (6 mg kg(-1)) and intravenous (2 mg kg(-1)) administration. Plasma samples were protein precipitated with acetonitrile using midazolam as internal standard. A UPLC HSS T3 chromatographic column was utilized for separation, with a mobile phase consisting of methanol-water-formic acid in gradient elution procedure. Quantitative analysis was performed using multiple reaction monitoring in electrospray positive-ion mode. Veliparib exhibited excellent linearity within the 1-1,000 ng mL(-1) range (r > 0.99). The intra- and inter-day precision of veliparib were both within 15%, and the accuracy ranged from 93.7 to 107.7%. The average recovery was above 86%, and the matrix effect was 89.0-95.8%. The AUC((0-t)) values for oral and intravenous administration were 1014.7 +/- 42.9 and 647.2 +/- 85.2 h ng mL(-1), respectively, resulting in a bioavailability of 52.3%. The UPLC-MS/MS method established in this study featured a low sample injection volume, a low quantification limit, a short chromatographic runtime, high sensitivity, and selectivity. The developed method can be used for the pharmacokinetic analysis of veliparib in both preclinical and clinical studies.

Phototherapy presents an effective approach for treating localized methicillin-resistant Staphylococcus aureus (MRSA) infections; however, the tradeoff between therapeutic efficacy and negative off-target effect persists. To address these issues, we have developed a nanoparticle-hydrogel superstructure comprising phototherapeutic liposomal nanobubbles (NB) and fat extract (FE) encapsulated by F-127 hydrogel. After local administration to sites of MRSA infection, the superstructure effectively neutralizes high levels of MRSA toxins to protect against toxin-mediated cytotoxicity through loaded, which can also be leveraged to enhance anti-MRSA efficacy via toxin-regulated on-demand phototherapy upon near-infrared irradiation. Meanwhile, the oxidative stress-induced injury to healthy cells can be mitigated by the FE. In a murine model of skin MRSA infection, treatment with the nanoparticle-hydrogel superstructure significantly reduces MRSA load, especially when combined with MRSA toxin for enhanced bacterial inhibition. Concurrently, this superstructure accelerates wound healing by enhancing angiogenesis and collagen deposition while reducing inflammation. Overall, the nanoparticle-hydrogel superstructure shows promise for treating local pathogen-infected wounds.

Recurrent vulvovaginal candidiasis (RVVC) is an opportunistic infection predominantly caused by Candida albicans (C. albicans) and is particularly prevalent among individuals on immunosuppressants. Currently, there are no FDA-approved therapies for specifically controlling RVVC, mainly due to the need for therapeutics against RVVC that require both antifungal treatments to resolve active infections and strategies to prevent recurrence. This study introduces a biomimetic photoimmunotherapeutic nanoplatform consisting of an adjuvant-encapsulated polymeric core stabilized by a photosensitizer-loaded vaginal epithelial cell membrane coating to treat and protect against RVVC. With its cell membrane camouflaging, the nanoplatforms target and enhance adherence to the intravaginal site of C. albicans infection, allowing the nanoplatform to resist being flushed away by vaginal fluids. Upon subsequent near-infrared irradiation, the nanoplatform's targeted photothermal power effectively eliminates C. albicans while minimizing thermal damage to surrounding healthy tissue. Postphotothermal treatment, the generated C. albicans-based debris and candidalysin-captured nanoplatform (serving as a nanotoxoid), along with adjuvant, are processed by resident antigen-presenting cells to promote multiantigenic immunity. This response provides protection against secondary intravaginal C. albicans infection (RVVC model) and C. albicans-induced systemic infection even under immunosuppressive conditions (septicemia model). Notably, anti-C. albicans antibodies produced in the pretreated mice exhibit comparable affinity to clinically isolated C. albicans strains, indicating potential for clinical application. Overall, this study underscores the potential of the proposed photoimmunotherapeutic nanoplatform for the effective treatment and prevention of RVVC.

Triple-negative breast cancer (TNBC) is resistant to most antitumor treatments, leaving chemotherapy as the primary option. Although doxorubicin (Dox) in combination with other therapies is promising for TNBC management, the combined effect is still compromised by the dose-limiting toxicities of Dox. Here, we developed a chemotherapeutic drug scavenger (CDS) by encapsulating GC-rich DNA—preferred binding targets of Dox—within an erythrocyte membrane functionalized with a normal tissue-targeting (NTT) peptide. Mimicking the structure of the cell nucleus, CDS selectively absorbs and neutralizes Dox in susceptible normal organs while sparing tumor tissues. This targeted detoxification allows for safe escalation of the Dox dose to 15 mg/kg, three times the standard 5 mg/kg, without observable toxicity. Such a high Dox dose enabled by CDS pretreatment significantly inhibited the post-operative residual/metastasized 4T1 tumor growth, regardless of the early or later stages of the tumor. Also, delivery of a high dose of Dox into the 4T1 tumor could profoundly increase the G2/M arrest, facilitating the combination therapy with a low-powered radiation of 2 Gy. Further, tumor exposure to high Dox amounts could convert the 4T1 tumor microenvironment from ‘cold’ to ‘hot’, leading to improved infiltration of immune cells, including T cells, dendritic cells, and macrophages. Overall, this study demonstrates how the safe injection of high amounts of Dox enabled by CDS detoxification could augment and extend Dox’s functionality combined with surgery, radiotherapy, and cell therapy for TNBC treatment.

Blood transfusions save lives and improve health every day. Despite the matching of blood types being stricter than it ever has been, emergency transfusions among incompatible blood types are still inevitable in the clinic when there is a lack of acceptable blood types for recipients. Here to overcome this, a counter measure nanoplatform consisting of a polymeric core coated by a red blood cell (RBC) membrane is developed. With A-type or B-type RBC membrane camouflaging, the nanoplatform is capable of specifically capturing anti-A or anti-B IgM antibodies within B-type or A-type whole blood, thereby decreasing the corresponding IgM antibody levels and then allowing the incompatible blood transfusions. In addition to IgM, the anti-RBC IgG antibody in a passive immunization murine model can likewise be neutralized by this nanoplatform, leading to prolonged circulation time of incompatible donor RBCs. Noteworthily, nanoplatform made by expired RBCs (>42 days stored hypothermically) and then subjected to lyophilization does not impair their effect on antibody neutralization. Most importantly, antibody-captured RBC-NP do not exacerbate the risk of inflammation, complement activation, and coagulopathy in an acute hemorrhagic shock murine model. Overall, this biomimetic nanoplatform can safely neutralize the antibody to enable incompatible blood transfusion.

Phototherapy is an effective strategy to control Candida albicans (C. albicans) infection without raising the concern of drug resistance. Despite its effectiveness, a higher dose of phototherapeutic power is required for C. albicans elimination compared to bacteria that have to be used, which is readily accompanied by off-target heat and toxic singlet oxygen to damage normal cells, thus limiting its usefulness for antifungal applications. Here to overcome this, we develop a "three-in-one" biomimetic nanoplatform consisting of an oxygen-dissolved perfluorocarbon camouflaged by a photosensitizer-loaded vaginal epithelial cell membrane. With a cell membrane coating, the nanoplatform is capable of specifically binding with C. albicans at the superficial or deep vaginal epithelium, thereby centering the phototherapeutic agents on C. albicans. Meanwhile, the cell membrane coating endows the nanoplatform to competitively protect healthy cells from candidalysin-medicated cytotoxicity. Upon candidalysin sequestration, pore-forming on the surface of the nanoplatform accelerates release of the preloaded photosensitizer and oxygen, resulting in enhanced phototherapeutic power for improved anti-C. albicans efficacy under near-infrared irradiation. In an intravaginal C. albicans-infected murine model, treatment with the nanoplatform leads to a significantly decreased C. albicans burden, particularly when leveraging candidalysin for further elevated phototherapy and C. albicans inhibition. Also, the same trends hold true when using the nanoplatform to treat the clinical C. albicans isolates. Overall, this biomimetic nanoplatform can target and bind with C. albicans and simultaneously neutralize the candidalysin and then transform such toxins that are always considered a positive part in driving C. albicans infection with the power of enhancing phototherapy for improved anti-C. albicans efficacy.

The pharmacological activities of dictamnine and fraxinellone have been well reported; however, only a few studies have focused on the pharmacokinetics and bioavailability of concomitant delivery of these drugs in vivo. To shed light on this neglected area, we developed a rapid and sensitive UPLC-MS/MS method that quantified the levels of dictamnine and fraxinellone simultaneously in rat plasma. This method was initiated by a one-step protein precipitation strategy to purify plasma samples collected from rats treated with either oral or intravenous administration of dictamnine and fraxinellone. The mobile phase contained acetonitrile and 0.1% formic acid at a steady flow rate of 0.6 mL/min. As a result, an excellent analyte peak resolution was achieved, and the entire process took only 3 min per sample. The results were indicative of the desired linearity (r2 ≥ 0.999), precision (RSD% was within 15%), accuracy (RE% was within 15%), recoveries (≥80.66 and 68.15% for dictamnine and fraxinellone, respectively) and matrix effects (≥94.66 and 91.37% for dictamnine and fraxinellone, respectively). Additionally, the detectable limits of these two compounds were both low even when they reached 5 ng/mL. Taken together, these findings contribute to a better understanding of the pharmacokinetics and bioavailability properties of concomitant delivery of dictamnine and fraxinellone.

An effective therapeutic strategy to treat vulvovaginal candidiasis (VVC) that is mainly caused by Candida albicans (C. albicans) infection is highly desirable. While Amphotericin B (AmB) has demonstrated promise, its precise localization to C. albicans burden at vaginal sites is oftentimes limited by the high fluidity microenvironment of the vagina, which can compromise treatment efficacy. To overcome this issue, a biomimetic AmB delivery system is developed, in which AmB preloaded polymeric cores are cloaked with vaginal epithelial cells membrane (VM-ANP). With its cell membrane coating, VM-ANP naturally targets and strongly binds with C. albicans, thus resisting the self-cleaning of vaginal fluid. Besides its long retention property, VM-ANP could penetrate deeply in vaginal tissue to achieve its full antifungal potential by attaching to hidden C. albicans. It is shown that both C. albicans suspension and biofilm biomass could be effectively inhibited by the VM-ANP in vitro. In a C. albicans intravaginal infection model, treatment with VM-ANP results in significantly decreased fungal challenges both in vaginal tissue and fluid. Overall, such biomimetic strategy adds the merit of natural cell membrane into the targeted delivery of drug in treating VVC, which also serves as a promising platform against vaginitis-related pathogens.

With its well-documented toxicity, the use of doxorubicin (Dox) for cancer treatment requires trade-offs between safety and effectiveness. This limited use of Dox also hinders its functionality as an immunogenic cell death inducer, thus impeding its usefulness for immunotherapeutic applications. Here, we develop a biomimetic pseudonucleus nanoparticle (BPN-KP) by enclosing GC-rich DNA within erythrocyte membrane modified with a peptide to selectively target healthy tissue. By localizing treatment to organs susceptible to Dox-mediated toxicity, BPN-KP acts as a decoy that prevents the drug from intercalating into the nuclei of healthy cells. This results in significantly increased tolerance to Dox, thereby enabling the delivery of high drug doses into tumor tissue without detectable toxicity. By lessening the leukodepletive effects normally associated with chemotherapy, dramatic immune activation within the tumor microenvironment was also observed after treatment. In three different murine tumor models, high-dose Dox with BPN-KP pretreatment resulted in significantly prolonged survival, particularly when combined with immune checkpoint blockade therapy. Overall, this study demonstrates how targeted detoxification using biomimetic nanotechnology can help to unlock the full potential of traditional chemotherapeutics.

An effective therapeutic strategy against methicillin-resistant Staphylococcus aureus (MRSA) that does not promote further drug resistance is highly desirable. While phototherapies have demonstrated considerable promise, their application toward bacterial infections can be limited by negative off-target effects to healthy cells. Here, a smart targeted nanoformulation consisting of a liquid perfluorocarbon core stabilized by a lipid membrane coating is developed. Using vancomycin as a targeting agent, the platform is capable of specifically delivering an encapsulated photosensitizer along with oxygen to sites of MRSA infection, where high concentrations of pore-forming toxins trigger on-demand payload release. Upon subsequent near-infrared irradiation, local increases in temperature and reactive oxygen species effectively kill the bacteria. Additionally, the secreted toxins that are captured by the nanoformulation can be processed by resident immune cells to promote multiantigenic immunity that protects against secondary MRSA infections. Overall, the reported approach for the on-demand release of phototherapeutic agents into sites of infection could be applied against a wide range of high-priority pathogens.

With few options available for the effective treatment of multidrug-resistant bacteria, photodynamic therapy (PDT) has emerged as a promising therapeutic strategy that does not promote the development of antibiotic resistance. Unfortunately, the beneficial bactericidal effect of PDT is oftentimes accompanied by the uncontrollable production of reactive oxygen species. To overcome this issue, a pore-forming toxin (PFT)-responsive biomimetic nanobubble is designed, which is constructed by co-encapsulating a perfluorocarbon nanoemulsion and a photosensitizer within the red blood cell membrane. It is shown that PFTs derived from three pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), group A Streptococcus (GAS), and Listeria monocytogenes (LM), can be effectively absorbed by the nanobubble. Upon toxin absorption, the formation of pores on the nanobubble surface allows the accelerated release of oxygen dissolved inside the nanoemulsion along with the photosensitizer, thus resulting in enhanced PDT and bactericidal efficacy. In three skin infection models, treatment with the nanobubbles results in significantly decreased lesion formation and reduced inflammation. In addition to oxygen, the platform can be used to deliver nitric oxide in a bacterial toxin-dependent manner. Overall, biomimetic nanobubbles may work as a broad gas delivery system that is capable of responding to a variety of PFT-based stimuli for precision PDT.

Objective The aim of this study is to develop a rapid and sensitive UPLC-MS/MS approach to determine the sophoridine (SOP) level in rat plasma and the pharmacokinetics of the substance. Significance Sophoridine is used as an anti-inflammatory, anti-virus, anti-microbial, and anti-tumor alkaloid. It is essential to explore specific detection methods for the quantitative analysis of SOP in the blood circulation. Methods The rat plasma samples were prepared by one-step protein precipitation with acetonitrile. Subsequently, the samples were separated by chromatography using a UPLC BEH C18 reversed-phase with an initial mobile phase of methanol and 0.1% formic acid aqueous solution. The gradient elution was performed at a fixed flow rate of 0.4 mL/min, and multiple reaction monitoring (MRM) mode with an electrospray positive ionization source was employed to detect the transitions of m/z 249.1 -> 84.2 for SOP and m/z 264.3 -> 69.8 for dendrobine (IS). The entire process required 3.5 min for each sample. Results A linear correlation was established over the range of 2-2000 ng/mL (r (2)>= 0.9954) for SOP in rat plasma with a lower limit of quantification (LLOQ) at 2 ng/mL. The range of accuracy was tested between 94.90% and 100.80%, and the relative standard deviations (RSDs) toward both intra- and inter-day precision were <10%. Thus, this method was successfully applied to a pharmacokinetic study, and the subsequent results demonstrated a low absolute bioavailability of 2.32%. Conclusion The present study established a reliable method that quantified the SOP concentration in rat plasma after administering a dose of 2 mg/kg intravenously or 20 mg/kg orally.

Myocardial fibrosis (MF) is one of the leading causes of end-stage heart disease. Many studies have confirmed that inflammation caused by aldosterone may play an important role in the process of MF. A selective 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme inhibitor can reduce the inactivation of cortisol, allowing cortisol to compete for mineralocorticoid receptors. This study investigated the protective effect of a novel selective 11βHSD2 inhibitor (WZ51) on MF and described its underlying mechanism. The administration of WZ51 in rats with MF significantly alleviated myocardial injury, accompanied by a decrease in lactate dehydrogenase and the creatine kinase myocardial band. Furthermore, WZ51 significantly inhibited the development of MF and increased the protein level of 11β-HSD2. The results of this study demonstrate that 11β-HSD2 plays an important pathological role in MF. Thus, WZ51 may be a potential therapeutic agent for the treatment of this condition.

Background The present study aimed to develop and validate a rapid, selective, and reproducible ultra-performance liquid chromatography-tandem mass spectrometry separation method for the simultaneous determination of the levels of parecoxib and its main metabolite valdecoxib in rat plasma. Moreover, this method was applied to investigate the pharmacokinetics of parecoxib and valdecoxib in rats. Methods Following the addition of celecoxib as an internal standard, one-step protein precipitation by acetonitrile was used for sample preparation. The effective chromatographic separation was carried out using an ACQUITY UPLC®BEH C18 reversed phase column (2.1 mm × 50 mm, 1.7 μm particle size) with acetonitrile and water (containing 0.1% formic acid) as the mobile phase. The procedure was performed in less than 3 min with a gradient elution pumped at a flow rate of 0.4 ml/min. The electrospray ionization source was applied and operated in the positive ion mode and multiple reaction monitoring mode was used for quantification using the following: target fragment ions: m/z 371 → 234 for parecoxib, m/z 315 → 132 for valdecoxib and m/z 382 → 362 for celecoxib. Results The method validation demonstrated optimal linearity over the range of 50–10,000 ng/ml (r 2 ≥ 0.9996) and 2.5–500 ng/ml (r 2 ≥ 0.9991) for parecoxib and valdecoxib in rat plasma, respectively. Conclusions The present study demonstrated a simple, sensitive and applicable method for the quantification of parecoxib and its main pharmacologically active metabolite valdecoxib following sublingual vein administration of 5 mg/kg parecoxib in rats.