A Platelet-Powered Drug Delivery System for Enhancing Chemotherapy Efficacy for Liver Cancer Using the Trojan Horse Strategy.

Optimizing the delivery and penetration of nano-sized drugs within liver cancer sites, along with remodeling the tumor microenvironment, is crucial for enhancing the efficacy of chemotherapeutic agents. For this study, a platelet (PLT)-mediated nanodrug delivery system (DASA+ATO@PLT) was developed to improve the effectiveness of chemotherapy. This system delivers nano-sized dasatinib and atovaquone specifically to liver tumor sites and facilitates intra-tumoral permeation upon release. Through JC-1, immunohistochemistry, and DNA damage analyses, the therapeutic effect of DASA+ATO@PLT was assessed. In vitro simulation and intravital imaging were carried out to determine the accumulation of dasatinib and atovaquone in liver tumor sites. The experiment demonstrated the accumulation of dasatinib and atovaquone in tumor sites, followed by deep permeation in the tumor microenvironment with the assistance of PLTs, while simultaneously revealing the ability of DASA+ATO@PLT to remodel the liver cancer microenvironment (overcoming hypoxia) and enhance chemotherapeutic efficacy. This system utilizes the natural tumor recognition ability of PLTs and enhances the chemo-immunotherapeutic effect through targeted delivery of nano-chemotherapeutic drugs to the tumor, resulting in effective accumulation and infiltration. The PLT-mediated nanodrug delivery system serves as a "Trojan horse" to carry therapeutic drugs as cargo and deliver them to target cells, leading to favorable outcomes.

Engineering tumor-oxygenated nanomaterials: advancing photodynamic therapy for cancer treatment.

Photodynamic therapy (PDT), a promising treatment modality, employs photosensitizers to generate cytotoxic reactive oxygen species (ROS) within localized tumor regions. This technique involves administering a photosensitizer followed by light activation in the presence of oxygen (O2), resulting in cytotoxic ROS production. PDT's spatiotemporal selectivity, minimally invasive nature, and compatibility with other treatment modalities make it a compelling therapeutic approach. However, hypoxic tumor microenvironment (TME) poses a significant challenge to conventional PDT. To overcome this hurdle, various strategies have been devised, including in-situ O2 generation, targeted O2 delivery, tumor vasculature normalization, modulation of mitochondrial respiration, and photocatalytic O2 generation. This review aims to provide a comprehensive overview of recent developments in designing tumor-oxygenated nanomaterials to enhance PDT efficacy. Furthermore, we delineate ongoing challenges and propose strategies to improve PDT's clinical impact in cancer treatment.

Platelets as delivery vehicles for targeted enrichment of NO· to cerebral glioma for magnetic resonance imaging.

Using a magnetic resonance imaging (MRI) contrast agent, MRI has made substantial contributions to glioma diagnosis. Metal-free MRI agents, such as the nano free radical nitric oxide (NO·) micelle, can overcome the inherent toxicity of metal-based agents in certain patient populations. However, the low spatial resolution of nano NO· micelle in MRI limits its clinical development. In this study, we pretreated platelets (PLTs) and loaded them with nano NO· micelles to synthesize NO·@PLT, which can overcome the low contrast and poor in vivo stability of nitroxide-based MRI contrast agents. The PLTs can serve as potential drug carriers for targeting and delivering nano NO· micelles to gliomas and thus increase the contrast in T1-weighted imaging (T1WI) of MRI. This drug carrier system uses the unique tumor-targeting ability of PLTs and takes advantage of the high signal presentation of steady nano NO· micelles in T1WI, thereby ultimately achieving signal amplification of glioma in T1WI. With the effect of PLTs-tumor cell adhesion, NO·@PLT has per-nitroxide transverse relativities of approximately 2-fold greater than those of free NO· particles. These features allow a sufficient NO·@PLT concentration to accumulate in murine subcutaneous glioma tumors up from 5 min to 2.5 h (optimum at 1.5 h) after systemic administration. This results in MRI contrast comparable to that of metal-based agents. This study established a promising metal-free MRI contrast agent, NO·@PLT, for glioma diagnosis, because it has superior spatial resolution owing to its high glioma-targeting ability and has significant translational implications in the clinic.

Advances in Targeting Drug Biological Carriers for Enhancing Tumor Therapy Efficacy.

Chemotherapy drugs continue to be the main component of oncology treatment research and have been proven to be the main treatment modality in tumor therapy. However, the poor delivery efficiency of cancer therapeutic drugs and their potential off-target toxicity significantly limit their effectiveness and extensive application. The recent integration of biological carriers and functional agents is expected to camouflage synthetic biomimetic nanoparticles for targeted delivery. The promising candidates, including but not limited to red blood cells and their membranes, platelets, tumor cell membrane, bacteria, immune cell membrane, and hybrid membrane are typical representatives of biological carriers because of their excellent biocompatibility and biodegradability. Biological carriers are widely used to deliver chemotherapy drugs to improve the effectiveness of drug delivery and therapeutic efficacy in vivo, and tremendous progress is made in this field. This review summarizes recent developments in biological vectors as targeted drug delivery systems based on microenvironmental stimuli-responsive release, thus highlighting the potential applications of target drug biological carriers. The review also discusses the possibility of clinical translation, as well as the exploitation trend of these target drug biological carriers.

Strategies to prolong drug retention in solid tumors by aggregating Endo-CMC nanoparticles.

Developing a highly effective nano-drug delivery system with sufficient drug permeability and retention in tumors is still a major challenge for oncotherapy. Herein, a tumor microenvironment responsive, aggregable nanocarriers embedded hydrogel (Endo-CMC@hydrogel) was developed to inhibit the tumoral angiogenesis and hypoxia for enhanced radiotherapy. The antiangiogenic drug (recombinant human endostatin, Endo) loaded carboxymethyl chitosan nanoparticles (Endo-CMC NPs) was wrapped by 3D hydrogel to comprise the Endo-CMC@hydrogel. After peritumoral injection, the Endo-CMC NPs were released, invaded deeply into the solid tumor, and cross-linked with intratumoral calcium ions. The cross-linking process enabled these Endo-CMC NPs to form larger particles, leading to long retention in tumor tissue to minimize premature clearance. This Endo-CMC@hydrogel, integrating the abilities of good tumoral penetration, long retention of anti-drug, and alleviation of hypoxia in tumor tissue, greatly improved the therapeutic effect of radiotherapy. This work provides a proof-of-concept of tumor microenvironment-responding and an aggregable nano-drug delivery system as promising antitumor drug carriers for effective tumor therapy.

Glucose-activatable insulin delivery with charge-conversional polyelectrolyte multilayers for diabetes care.

One of the most effective treatments for diabetes is to design a glucose-regulated insulin (INS) delivery system that could adjust the INS release time and rate to reduce diabetes-related complications. Here, mixed multiple layer-by-layer (mmLbL)-INS microspheres were developed for glucose-mediated INS release and an enhanced hypoglycemic effect for diabetes care. To achieve ultrafast glucose-activated INS release, glucose oxidase (GOx) was assembled with a positively charged polymer and modified on INS LbL. The mmLbL-INS microspheres were constructed with one, two, and four layers of the polyelectrolyte LbL assembly at a ratio of 1:1:1. Under hyperglycemia, GOx converts a change in the hyperglycemic environment to a pH stimulus, thus providing sufficient hydrogen ion. The accumulated hydrogen ion starts LbL charge shifting, and anionic polymers are converted to cationic polymers through hydrolytic cleavage of amine-functionalized side chains. The results of in vitro INS release suggested that glucose can modulate the mmLbL-INS microspheres in a pulsatile profile. In vivo studies validated that this formulation enhanced the hypoglycemic effect in STZ-induced diabetic rats within 2 h of subcutaneous administration and facilitated stabilization of blood glucose levels for up to 2 days. This glucose-activatable LbL microsphere system could serve as a powerful tool for constructing a precisely controlled release system.

A Closed-Loop Autologous Erythrocyte-Mediated Delivery Platform for Diabetic Nephropathy Therapy.

Failure to control blood glucose level (BGL) may aggravate oxidative stress and contribute to the development of diabetic nephropathy (DN). Using erythrocytes (ERs) as the carriers, a smart self-regulatory insulin (INS) release system was constructed to release INS according to changes in BGLs to improve patients' compliance and health. To overcome the limited sources of ERs and decrease the risk of transmitting infections, we developed an in vitro, closed-loop autologous ER-mediated delivery (CAER) platform, based on a commercial hemodialysis instrument modified with a glucose-responsive ER-based INS delivery system (GOx-INS@ER). After the blood was drained via a jugular vein cannula, some of the blood was pumped into the CAER platform. The INS was packed inside the autologous ERs in the INS reactor, and then their surface was modified with glucose oxidase (GOx), which acts as a glucose-activated switch. In vivo, the CAER platform showed that the BGL responsively controlled INS release in order to control hyperglycemia and maintain the BGL in the normal range for up to 3 days; plus, there was good glycemic control without the added burden of hemodialysis in DN rabbits. These results demonstrate that this closed-loop extracorporeal hemodialysis platform provides a practical approach for improving diabetes management in DN patients.

Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin.

BACKGROUND: Circular RNA (circRNA) is crucial to the progression of hepatocellular cancer (HCC). In addition, Mitochondrial calcium uniporter regulatory factor 1 (MCUR1) is commonly overexpressed in HCC to increase cellular ATP levels. Due to the highly aggressive characteristics of HCC, it is essential to identify new diagnostic biomarkers and therapeutic targets that may facilitate the diagnosis of HCC and the development of effective anti-HCC treatments. METHODS: A series of in vitro and in vivo experiments were undertaken to investigate the biological importance and underlying mechanisms of circ_0000098 in HCC. RESULTS: The expression of circ_0000098 was higher in HCC tissues compared to paired adjacent tissues. According to the receiver-operating characteristic curves, circ_0000098 functioned as a potential diagnostic tumor marker in HCC. Our experiments indicated that circ_0000098 served as a key oncogenic circRNA to increase HCC cell proliferation and invasion in vitro and HCC progression in vivo. Furthermore, mechanistic investigation demonstrated that by sequestering miR-383 from the 3'-UTR of MCUR1, circ_0000098 positively regulated MCUR1 expression in HCC cells and finally promoted HCC progression. On the other hand, inhibiting circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing P-glycoprotein (P-gp, MDR1) expression and intracellular ATP levels. Either downregulation of MCUR1 or overexpression of miR-383 improved DOX sensitivity in HCC cells. Subsequently, a short hairpin RNA targeting circ_0000098 (referred to as sh-1) and doxorubicin (DOX) were encapsulated into platelets (PLTs), referred to as DOX/sh-1@PLT. Activated DOX/sh-1@PLT through HCC cells resulted in the creation of platelet-derived particles that were capable of delivering the DOX/sh-1 combination into HCC cells and promoting intracellular DOX accumulation. Furthermore, our in vivo experiments showed that DOX/sh-1@PLT can effectively reduce P-gp expression, promote DOX accumulation, and reverse DOX resistance. CONCLUSIONS: Our results demonstrated that circ_0000098 is an oncogenic circRNA that promotes HCC development through the miR-383/MCUR1 axis and targeting circ_0000098 with DOX/sh-1@PLT may be a promising and practical therapeutic strategy for preventing DOX resistance in HCC.

Ultrasound-Triggered On-Demand Insulin Release for Diabetes Mellitus Treatment.

Exogenous insulin (INS) is successfully used for controlling glucose in diabetic patients. Although frequent INS injections can overcome hyperglycemia, they are both painful and inconvenient. Herein, we report an ultrasound-regulated INS release platform (INS-PPIX@ER hydrogel) that allows for remotely regulated on-demand INS release and minimizes pain. In this system, protoporphyrin IX (PPIX)-containing erythrocytes (ERs) served as an INS reservoir, an injectable peptide hydrogel provided strong protection for the ERs, and INS release was regulated using ultrasound. This particular INS release behavior was triggered by increased production of reactive oxygen species (ROS) by PPIX from the PPIX-loaded ERs under ultrasound irradiation. The ROS then interacted with the phospholipid bilayer of the ERs, thereby opening the stomata of the INS-PPIX@ER and releasing INS. INS-PPIX@ER hydrogels could control hyperglycemia within 2 h and maintained normal blood glucose levels for up to 3 days. This effective remote approach allowed closed-loop drug release spatiotemporally without causing any pain and injury. Our findings could serve as a powerful tool for constructing a precisely controlled release system.

Relieving immunosuppression by Endo@PLT targeting anti-angiogenesis to improve the efficacy of immunotherapies.

Low levels of immune infiltrates in the tumor milieu hinder the effectiveness of immunotherapy against immune-cold tumors. In the current work, a tumor-targeting drug delivery system composed of Endo-loaded platelets (Endo@PLT) was developed to relieve immunosuppression by achieving tumor vascular normalization. Endo@PLT reprogrammed the immunostimulatory phenotype, achieving excellent PD-1 immunotherapy in vivo.

Erythrocyte-mimicking subcutaneous platform with a laser-controlled treatment against diabetes.

Exogenous insulin (INS) is critical for managing diabetes. However, owing to its short in vivo half-life, frequent injection of INS is un-avoidable, which is both painful and inconvenient, compromising the quality of life. Herein, we developed a laser-regulated INS release system (INS-ICG@ER hydrogel) that allowed an on-demand release of INS from the subcutaneous INS reservoir by remote laser control without the frequent injection of INS. The amino acid hydrogel functions as a hydrogel 3D scaffold material, which offers increased subcutaneous stability of drug loaded erythrocytes (ER). This INS-ICG@ER hydrogel would release INS due to the elevated content of reactive oxygen species (ROS), generated by ICG under laser irritation. Conversely, the ROS would be scavenged without the laser irradiation and stopped the release of INS from INS-ICG@ER hydrogel. Furthermore, the release of INS from INS-ICG@ER hydrogel could be regulated by laser irradiation. The INS-ICG@ER hydrogels could control the hyperglycemia within 2 h in diabetic mice and maintained their normal blood glucose level (BGL) for up to 6 days with laser irradiation 30 min prior to meals avoiding the frequent injection of free INS. This delivery system is an effective method that offers a spatiotemporally controlled release of INS to control the glucose level in vivo.

Bi-enzymes treatments attenuate cognitive impairment associated with oxidative damage of heavy metals.

Oxidative stress has been implicated in the pathogenesis of cognitive impairment. Lead (Pb) is a common environmental toxicant and plays a vital role in oxidative stress activation. In this study, a superoxide dismutase (SOD) and catalase (CAT) containing poly (lactic-co-glycolic acid) (PLGA) meso-particles (PLGA@SOD-CAT) were prepared to attenuate cognitive impairment via inhibiting oxidative stress in rats. It was prepared using a double emulsion (water/oil/water phase) technique to minimize the hazardous effects of Pb burden on cognitive impairment. The meso-particles antagonized the Pb-induced cognitive impairments. Behaviour, serum biochemical parameters and biomarkers of oxidative stress in rats were evaluated after they were subjected to intravenous injection with lead nitrate and PLGA@SOD-CAT. Moreover, the potential protective mechanism of PLGA@SOD-CAT was determined. Notably, PLGA@SOD-CAT appreciably agented memory impairment caused by lead nitrate and it could significantly inhibit Pb-induced oxidative stress in the blood. Furthermore, a remarkable reversion effect of cognitive impairments, including escape latency, crossing platform times and time per cent during the platform quadrant, after PLGA@SOD-CAT administration were noted. Therefore, these results suggested that the bi-enzymes platform was a superior product in eliminating Pb-induced cognitive impairments through reducing expression of Pb-associated oxidative stress, and it could potentially be applied in detoxifying heavy metals in blood circulation.

Au-Hemoglobin Loaded Platelet Alleviating Tumor Hypoxia and Enhancing the Radiotherapy Effect with Low-Dose X-ray.

Radiotherapy (RT) is a widely explored clinical modality to combat cancer. However, its therapeutic efficacy is not always satisfied because of the severe hypoxic microenvironment in solid tumors and the high dosage of radiation harmful to the adjacent healthy tissue. Herein, Au nanoparticle-hemoglobin complex nanoparticle loaded platelets (Au-Hb@PLT) were fabricated. These Au-Hb@PLT would be activated by tumor cells, and the formed platelet-derivate particles (PM) could deliver Au nanoparticle-hemoglobin complex deeply into tumor tissue because of their small size and tumor homing ability. Hemoglobin acts as an oxygen carrier to relieve the hypoxia and gold nanoparticles work as radiosensitizers to potentiate the sensitivity of tumor cells to X-ray, thus, enhancing the in vivo therapeutic outcome even under a low-dose RT in tumor bearing mice. The enhanced antitumor effect and survival benefits endowed by the Au-Hb@PLT were confirmed in vitro and in vivo. These results demonstrate that these Au-Hb@PLT can work as an oxygen vehicle, offer a promising approach to mitigate hypoxia and improve RT efficacy with a low RT dosage.

Overcoming Hypoxia-Restrained Radiotherapy Using an Erythrocyte-Inspired and Glucose-Activatable Platform.

Radiotherapy (RT) as one of the most powerful cancer treatment strategies has been greatly restricted by tumor hypoxia. A mounting effort has been devoted to develop oxygen delivery systems for boosting the RT effect. Unluckily, those systems only supplied modest oxygen, which could not afford more than once and long-time RT. Herein, we describe the development of a glucose-regulated drug release platform, allowing for a long-term tumor normoxic microenvironment and repeated RT for a long time. The repeated cycles resulted in sustained high Endostar plasma levels, which dramatically normalized the tumor vasculature and chronically reversed tumor hypoxia. Taking advantage of the inexhaustible supply of oxygen, Endo@GOx-ER enabled RT achieved an impressive cancer treatment output. To the best of our knowledge, our strategy is the initial attempt to overcome tumor-hypoxia-limited RT through the normalization of tumor vasculature by using an erythrocyte-inspired and glucose-activatable platform and it visually casts a light on the clinical development.

Neutrophil membranes coated, antibiotic agent loaded nanoparticles targeting to the lung inflammation.

Natural cellular membranes, with the outstanding qualities of biocompatibility and specificity, have gained growing attentions in the system of drug delivery. Nanoparticles coated with cellular membranes are starting to be applied as drug-loaded-vehicles to target tumors. Here, neutrophil membranes were selected to apply in the treatment of inflammation because neutrophils can participate in various inflammatory responses and accumulate at inflammatory sites to eliminate pathogens. Through extracting neutrophil membranes from natural neutrophils without affecting their biological properties, nanoparticles loaded with sparfloxacin (SPX) were coated with these membranes and disguised as neutrophils. Compared with traditional nano-medicines, the neutrophil membrane-coated nanoparticles (NM-NP-SPX) possessed precise targeting ability just like the neutrophils could accumulate at inflammatory sites when inflammation burst. In addition, NM-NP-SPX could prolong the circulation time and had the property of controlled-release. Through in vivo experiments, we found that the concentration of three representative inflammatory cytokines in blood, bacteria and inflammatory cells in lungs of the mice with pneumonia reduced significantly in the initial 24 h after the injection of NM-NP-SPX, which meant that NM-NP-SPX could greatly reduce the risk of death for the patients with inflammation. Moreover, the infected lungs could recover rapidly without any side effects to other organs due to the low cytotoxicity of NM-NP-SPX against normal cells. Therefore, our developed drug delivery system has enormous advantages in treating inflammations. Not only that, this kind of bionic method may have greater value and application prospects in curing the inflammations arisen from cancers.

SQSTM1/p62 is involved in docosahexaenoic acid-induced cellular autophagy in glioblastoma cell lines.

Docosahexaenoic acid (DHA) is the most abundant n-3 polyunsaturated fatty acid in the human brain and works as an anticancer agent to induce cell cycle arrest and apoptosis in glioblastoma multiforme (GBM) cell lines. However, little is known about the connection between DHA and autophagy in GBM cells. We found that high-dose DHA caused cellular autophagy in cultured U251 and U118 GBM cell lines, but there was no effect with a low dose. Moreover, after treatment with a high dose of DHA at 12, 24, and 48 h, the protein expression of SQSTM1/p62 decreased in DHA-treated U251 cells at 12 and 24 h, but increased at 48 h, while in DHA-treated U118 cells, the protein expression increased at all time points. Interestingly, the level of SQSTM1/p62 mRNA was elevated in both DHA-treated U251 and U118 cells at all time points, indicating that DHA activated SQSTM1/p62 transcription in both cell lines. Furthermore, downregulation of SQSTM1/p62 by siRNA attenuated DHA-induced cellular autophagy in both cell lines. This report confirms that high-dose DHA induces cellular autophagy in GBM cells, and demonstrates that SQSTM1/p62 acts as a regulator and participates in DHA-induced autophagy.

Ultrafast glucose-responsive, high loading capacity erythrocyte to self-regulate the release of insulin.

Insulin (INS) delivery system that can mimic normal insulin secretion to maintain the blood glucose level (BGL) in the normal range is an ideal treatment for diabetes. However, most of the existing closed-loop INS delivery systems respond slowly to the changes in BGL, resulting in a time lag between the abnormal BGL and the release of INS, which is not suitable for practical application. In this study, glucose oxidase (GOx)-modified erythrocytes are used as INS carriers (GOx-INS-ER) that can rapidly self-regulate the release of INS upon the changes in BGL. In this system, glucose can be broken down into gluconic acid and hydrogen peroxide by GOx-INS-ER, and the latter will rupture the erythrocyte membrane to release INS within minutes. A pulsatile release of INS can be achieved upon the changes in the glucose concentration. This GOx-INS-ER enables diabetic rats to overcome hyperglycemia within 1 h, and a single injection of this GOx-INS-ER into the STZ-induced diabetic rats can maintain the BGL in the normal range up to 9 days. STATEMENT OF SIGNIFICANCE: Diabetes mellitus has been a major public health threatener with global prevalence. Although, glucose-responsive carriers that can release insulin (INS) in a closed loop have been explored greatly in recent years, their sluggish glucose-responsive property and low INS-loading content greatly restrict their practical application [ACS Nano, 2013, 7, 4194]. In this work, we reported INS-loaded erythrocytes featuring ultrafast glucose-responsive property and high INS loading content, which could release INS in a closed loop. These GOX-INS-ERs could respond to the changes in glucose level within several minutes and self-regulate the release of INS for a long time. Single injection of GOX-INS-ER can overcome hyperglycemia in diabetic mice within 1 h and maintain the baseline level of glucose up to 9 days. We think our method may provide a robust way to potentiate diabetes treatment.

Extracorporeal magnetic approach to reduce the unwanted side-effects and improve antibacterial activity of Ag/Fe3 O4 nanocomposites in rat.

While Ag nanoparticles hold great promise for broad spectrum antibacterial activity, the potential risks of Ag nanoparticles (NPs) on human health remain a challenge. In this study, Ag/Fe3 O4 composites have been successfully prepared and characterized by transmission electron microscopy, X-ray powder diffraction, and Fourier-transform infrared spectroscopy, and their magnetic and antibacterial properties have been assessed. In vivo results show that the antibacterial effect of 500 µg/mL Ag/Fe3 O4 nanocomposites was significantly higher than that of 1000 µg/mL AgNPs after 72 h of treatment (p < 0.01). Hematoxylin and eosin (HE) staining showed that squamous epithelium and dermis collagen fibers formed in the Ag/Fe3 O4 group after 8 days treatment. Wound closure was significantly better for the Ag/Fe3 O4 group than for the AgNPs group. On the other hand, there was less Ag in blood, liver, and kidney in the Ag/Fe3 O4 group, as more Ag was retained in the wound. According to lactate dehydrogenase, γ-glutamyl transpeptidase, and reactive oxygen species results, Ag/Fe3 O4 nanocomposites caused less unwanted side-effects. This work presents a new paradigm to reduce the unwanted side-effects of AgNPs and improve their antibacterial activity, providing a new avenue for wound healing. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2029-2036, 2018.

Membrane-Active Hydantoin Derivatives as Antibiotic Agents.

Hydantoin (imidazolidinedione) derivatives such as nitrofurantoin are small molecules that have aroused considerable interest recently due to their low rate of bacterial resistance. However, their moderate antimicrobial activity may hamper their application combating antibiotic resistance in the long run. Herein, we report the design of bacterial membrane-active hydantoin derivatives, from which we identified compounds that show much more potent antimicrobial activity than nitrofurantoin against a panel of clinically relevant Gram-positive and Gram-negative bacterial strains. These compounds are able to act on bacterial membranes, analogous to natural host-defense peptides. Additionally, these hydantoin compounds not only kill bacterial pathogens rapidly but also prevent the development of methicillin-resistant Staphylococcus aureus (MRSA) bacterial resistance under the tested conditions. More intriguingly, the lead compound exhibited in vivo efficacy that is much superior to vancomycin by eradicating bacteria and suppressing inflammation caused by MRSA-induced pneumonia in a rat model, demonstrating its promising therapeutic potential.