THE SURFACE STATE OF MACROPHAGE MEMBRANE UNDER THE ACTION OF Ca^(2+) AND Con A.

The effects of Ca2+ and Con A on the membrane surface of macrophage were studied by STM. Higher peaks correspond to the membrane proteins which were aggregated. Some band-like and lower furrows were expressed in the domain of membrane lipids.

Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis

The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases.Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment.However,only a limited number of nanotherapies have enter clinical trials or are clinically approved.Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system(MPS),resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors.Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy.Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages.Polymer conjugation revived the parent camptothecin agent(e.g.,7-ethyl-10-hydroxy-camptothecin),enabling lipid nanoparticle encapsulation.Furthermore,macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin,increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy.When tested in a preclinical murine model of breast cancer,macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles.Furthermore,intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity.Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity.This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.

Wrapping collagen-based nanoparticle with macrophage membrane for treating multidrug-resistant bacterial infection

Nowadays,multidrug-resistant(MDR)bacterial infectious diseases has become a thorny issue in the healthcare field.Owning to its intrinsic merits,photodynamic therapy(PDT)shows tremendous strengths in fighting against MDR bacterial infections.However,most photodynamic nanoplatforms exhibit unsatisfactory targeting efficiency towards bacteria and infection site,which may compromise the bactericidal effect of PDT.Herein,we firstly reported a bacteria-targeted collagen-based nanoparticle,named Ce6/Col/MM,for treating methicillin-resistant Staphylococ-cus aureus(MRSA)-infected wound.Ce6/Col/MM was fabricated by wrapping chlorin e6(Ce6)-loaded collagen-based nanoparticles with macrophage membrane(MM),showing excellent photodynamic activity and good biocompat-ibility.In vitro studies demonstrated that Ce6/Col/MM could target to bacteria and then exhibit prominent antibacterial capacity against planktonic MRSA under light irradiation.Furthermore,the treatment of MRSA-infected wound in mice with Ce6/Col/MM plus light illumination resulted in potent bacterial inactivation and accelerated wound healing,accompanied by favorable histological compatibility.Collectively,Ce6/Col/MM with superior targeting ability towards bacteria,effective photodynamic antibacterial potency and minimal safety concerns,might be a powerful bactericidal nanoagent for treating infections caused by MDR bacteria。

Radiation Effects on the Immunological Functions and Membranes of Alveolar Macrophages of Rats

Alveolar macrophages (AM) from BCG activated Wistar rat were irradiated with different doses of Gamma rays in vitro. The effects of radiation on their immunological functions and membrane damage were studied. The non-specific cytotoxicity and specific phagocytosis of AM irradiated with dose of 0, 100, 300 and 500 Gy decreased with the increase in dose. The relative fractions of Lactate Dehydrogenase and Beta-glucuronidase (β-glu) activity in supernatant increased with the increase in dose. There was a correlation between the suppression of immunological functions and the degree of damage of cytoplasmic and lysosomal membranes of AM after irradiation. Na2SeO3, a protective agent of cell membranes, alleviated this effect on the suppressive cytotoxicity indices of irradiated AM.

Sodium alginate and naloxone loaded macrophage-derived nanovesicles for the treatment of spinal cord injury

Spinal cord injury(SCI)causes Ca^(2+) overload,which can lead to inflammation and neuronal apoptosis.In this study,we prepared a nanovesicle derived from macrophage membrane(MVs),which encapsulated sodium alginate(SA)and naloxone(NAL)to inhibit inflammation and protect neurons by reducing the free Ca^(2+) concentration at the SCI site.Based on the transmission electron microscopy(TEM)image,the encapsulated sample(NAL–SA–MVs)had a particle size of approximately 134±11 nm and exhibited a sustained release effect.The encapsulation rate of NAL and SA was 82.07%±3.27%and 72.13%±2.61%in NAL–SA–MVs,respectively.Targeting tests showed that the NAL–SA–MVs could accumulate in large quantities and enhance the concentration of SA and NAL at the lesion sites.In vivo and in vitro studies indicated that the NAL–SA–MVs could decrease the concentration of free Ca^(2+),which should further alleviate the inflammatory response and neuronal apoptosis.Anti-inflammation results demonstrated that the NAL–SA–MVs could reduce the pro-inflammation factors(iNOS,TNF-α,IL-1β,IL-6)and increase the expression of antiinflammation factors(IL-10)at the cell and animal level.Concurrently,fluorescence,flow cytometry and western blot characterization showed that the apoptotic condition of the neurons was significantly inhibited.In addition,the motor function of C57 mice were significantly improved after NAL–SA–MVs treatment.In conclusion,it is suggested that the NAL–SA–MVs has tremendous potential in the treatment of SCI.

Cytokine nanosponges suppressing overactive macrophages and dampening systematic cytokine storm for the treatment of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis(HLH)is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction.Inspired by macrophage membranes harbor the receptors with special high affinity for proin-flammation cytokines,lipopolysaccharide(LPS)-stimulated macrophage membrane-coated nanoparticles(LMNP)were developed to show strong sponge ability to both IFN-γand IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo.Besides,LMNP also efficiently alleviated HLH-related symptoms including cytopenia,hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models.Furthermore,its sponge effect also worked well for five human HLH samples in vitro.Altogether,it’s firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation,which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.

Intravenous route to choroidal neovascularization by macrophage-disguised nanocarriers for mTOR modulation

Retinal pigment epithelial(RPE) is primarily impaired in age-related macular degeneration(AMD), leading to progressive loss of photoreceptors and sometimes choroidal neovascularization(CNV). mTOR has been proposed as a promising therapeutic target, while the usage of its specific inhibitor,rapamycin, was greatly limited. To mediate the mTOR pathway in the retina by a noninvasive approach, we developed novel biomimetic nanocomplexes where rapamycin-loaded nanoparticles were coated with cell membrane derived from macrophages(termed as MRaNPs). Taking advantage of the macrophage-inherited property, intravenous injection of MRaNPs exhibited significantly enhanced accumulation in the CNV lesions, thereby increasing the local concentration of rapamycin. Consequently, MRaNPs effectively downregulated the mTOR pathway and attenuate angiogenesis in the eye. Particularly, MRaNPs also efficiently activated autophagy in the RPE, which was acknowledged to rescue RPE in response to deleterious stimuli. Overall, we design and prepare macrophage-disguised rapamycin nanocarriers and demonstrate the therapeutic advantages of employing biomimetic cell membrane materials for treatment of AMD.

An ischemic area-targeting,peroxynitrite-responsive,biomimetic carbon monoxide nanogenerator for preventing myocardial ischemia-reperfusion injury

Myocardial ischemia-reperfusion (MI/R) injury is common in patients who undergo revascularization therapy for myocardial infarction, often leading to cardiac dysfunction. Carbon monoxide (CO) has emerged as a therapeutic molecule due to its beneficial properties such as anti-inflammatory, anti-apoptotic, and mitochondrial biogenesis-promoting properties. However, its clinical application is limited due to uncontrolled release, potential toxicity, and poor targeting efficiency. To address these limitations, a peroxynitrite (ONOO )-triggered CO donor (PCOD585) is utilized to generate a poly (lactic-co-glycolic acid) (PLGA)-based, biomimetic CO nanogenerator (M/PCOD@PLGA) that is coated with the macrophage membrane, which could target to the ischemic area and neutralize proinflammatory cytokines. In the ischemic area, local produced ONOO triggers the continuous release of CO from M/PCOD@PLGA, which efficiently ameliorates MI/R injury by clearing harmful ONOO , attenuating the inflammatory response, inhibiting cardiomyocyte apoptosis, and promoting mitochondrial biogenesis. This study provides a novel insight into the safe therapeutic use of CO for MI/R injury by utilizing a novel CO donor combined with biomimetic technology. The M/PCOD@PLGA nanogenerator offers targeted delivery of CO to the ischemic area, minimizing potential toxicity and enhancing therapeutic efficacy.

ROS-responsive biomimetic nanoparticles for potential application in targeted anti-atherosclerosis

The development of nanomedicines provides new opportunities for the treatment of atherosclerosis(AS)due to their great advantages such as the improved drug solubility,enhanced bioavailability and reduced side effects.Despite these advantages,nanomedicines are still facing some challenges.The problems remain in the short circulation life,lack of specific targeting and poor drug release controllability.In order to overcome the shortages of conventional nanomedicines,the combination of biomimetic strategy with smart nanoagents has been proposed.In light with the high reactive oxygen species(ROS)level in AS microenvironment and the fact that macrophages play a critical role in the pathogenesis of AS,we fabricated ROS-responsive biomimetic nanoparticles(NPs),which camouflaged macrophage membrane(MM)on ROS-responsive NPs loaded with rapamycin(RNPs)for potential application in AS therapy.The resulting ROSresponsive biomimetic NPs(MM/RNPs)exhibited favorable hydrodynamic size with negative surface charge,retained the functional proteins from MM,and showed ROS-responsive drug release.Because of the biomimetic camouflaging on surface,MM/RNPs could effectively escape from macrophages uptake and target to inflammatory endothelial cells.Meanwhile,MM/RNPs could inhibit the proliferation of macrophages and smooth muscle cells in vitro.Furthermore,the MM-coated NPs were found to be nontoxic in both cytotoxicity assay and in vivo toxicity evaluation.Consequently,these results demonstrated that MM/RNPs could be a potential candidate of drug delivery system for safe and effective anti-AS applications.

A pH-responsive biomimetic drug delivery nanosystem for targeted chemo-photothermal therapy of tumors

Smart drug delivery nanosystem is significant for tumor treatments due to its possibility of temporally,spatially,and dose-controlled release.However,the therapeutic efficacy of drug delivery nanosystem is often compromised in cancer treatment as the enrichment of therapeutic agents in the reticuloendothelial system.Herein,doxorubicin(DOX)loaded biomimetic drug delivery nanosystem with macrophage cell membrane(MCM)camouflaged,MnFe_(2)O_(4)-DOX-MCM nanocube(NC),is developed for cancer treatment with tumor targeting,pH-stimuli drug release,and chemo-photothermal therapeutic effects.The nanosystem shows the capability of immune escape and enhanced cellular uptake of cancer cells due to the MCM decoration.Acid-labile bond between the MnFe2O4 NCs and DOX remains stable at physiological condition and release drugs immediately in response to the endo-/lysosome pH stimuli.Meanwhile,the photothermal effect of the nanosystem destroys tumor tissue,which further promotes chemotherapeutic efficacy.In vivo results demonstrate the tumor homing ability and produce a notable synergistic therapeutic effect of the NCs.Thus,biomimetic pH-responsive drug delivery nanosystem,MnFe_(2)O_(4)-DOX-MCM NCs,is an effective nanoplatform,which might be potential application for cancer synergistic treatment.