Enhancing Glioblastoma Immunotherapy with Integrated Chimeric Antigen Receptor T Cells through the Re-Education of Tumor-Associated Microglia and Macrophages.

Glioblastoma (GBM) is an aggressive brain cancer that is highly resistant to treatment including chimeric antigen receptor (CAR)-T cells. Tumor-associated microglia and macrophages (TAMs) are major contributors to the immunosuppressive GBM microenvironment, which promotes tumor progression and treatment resistance. Hence, the modulation of TAMs is a promising strategy for improving the immunotherapeutic efficacy of CAR-T cells against GBM. Molecularly targeting drug pexidartinib (PLX) has been reported to re-educate TAMs toward the antitumorigenic M1-like phenotype. Here, we developed a cell-drug integrated technology to reversibly conjugate PLX-containing liposomes (PLX-Lip) to CAR-T cells and establish tumor-responsive integrated CAR-T cells (PLX-Lip/AZO-T cells) as a combination therapy for GBM. We used a mouse model of GBM to show that PLX-Lip was stably maintained on the surface of PLX-Lip/AZO-T cells in circulation and these cells could transmigrate across the blood-brain barrier and deposit PLX-Lip at the tumor site. The uptake of PLX-Lip by TAMs effectively re-educated them into the M1-like phenotype, which in turn boosted the antitumor function of CAR-T cells. GBM tumor growth was completely eradicated in 60% of the mice after receiving PLX-Lip/AZO-T cells and extended their overall survival time beyond 50 days; in comparison, the median survival time of mice in other treatment groups did not exceed 35 days. Overall, we demonstrated the successful fusion of CAR-T cells and small-molecule drugs with the cell-drug integrated technology. These integrated CAR-T cells provided a superior combination strategy for GBM treatment and presented a reference for the construction of integrated cell-based drugs.

Spatiotemporally Controlled T-Cell Combination Therapy for Solid Tumor.

Due to multidimensional complexity of solid tumor, development of rational T-cell combinations and corresponding formulations is still challenging. Herein, a triple combination of T cells are developed with Indoleamine 2,3-dioxygenase inhibitors (IDOi) and Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). To maximize synergism, a spatiotemporally controlled T-cell engineering technology to formulate triple drugs into one cell therapeutic, is established. Specifically, a sequentially responsive core-shell nanoparticle (SRN) encapsulating IDOi and CDK4/6i is anchored onto T cells. The yielded SRN-T cells migrated into solid tumor, and achieved a 1st release of IDOi in acidic tumor microenvironment (TME). Released IDOi restored tryptophan supply in TME, which activated effector T cells and inhibited Tregs. Meanwhile, 1st released core is internalized by tumor cells and degraded by glutathione (GSH), to realize a 2nd release of CDK4/6i, which induced up-regulated expression of C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine ligand 5 (CCL5), and thus significantly increased tumor infiltration of T cells. Together, with an enhanced recruitment and activation, T cells significantly suppressed tumor growth, and prolonged survival of tumor-bearing mice. This study demonstrated rationality and superiority of a tri-drug combination mediated by spatiotemporally controlled cell-engineering technology, which provides a new treatment regimen for solid tumor.

An elastase-inhibiting, plaque-targeting and neutrophil-hitchhiking liposome against atherosclerosis.

Neutrophil extracellular traps (NETs) play a crucial role in the formation of vulnerable plaques and the development of atherosclerosis. Alleviating the pathological process of atherosclerosis by efficiently targeting neutrophils and inhibiting the activity of neutrophil elastase to inhibit NETs is relatively unexplored and is considered a novel therapeutic strategy with clinical significance. Sivelestat (SVT) is a second-generation competitive inhibitor of neutrophil elastase with high specificity. However, therapeutic effect of SVT on atherosclerosis is restricted because of the poor half-life and the lack of specific targeting. In this study, we construct a plaque-targeting and neutrophil-hitchhiking liposome (cRGD-SVT-Lipo) to improve the efficacy of SVT in vivo by modifying the cRGD peptide onto SVT loaded liposome, which was based on the interaction between cRGD peptide and integrin ανß3 on the surface of cells in blood and plaque, including epithelial cell, macrophage and neutrophils. The cRGD-SVT-Lipo could actively tend to or hitchhike neutrophils in situ to reach atherosclerotic plaque, which resulted in enhanced atherosclerotic plaque delivery. The cRGD-SVT-Lipo could also reduce plaque area, stabilize plaque, and ultimately alleviate atherosclerosis progression through efficiently inhibiting the activity of neutrophil elastase in atherosclerotic plaque. Therefore, this study provides a basis and targeting strategy for the treatment of neutrophil-related diseases. STATEMENT OF SIGNIFICANCE: Neutrophil extracellular traps (NETs)-inhibiting is a prospective therapeutic approach for atherosclerosis but has received little attention. The NETs can be inhibited by elastase-restraining. In this work, an intriguing system that delivers Sivelestat (SVT), a predominantly used neutrophil elastase inhibitor with poor targeting capability, is designed to provide the drug with plaque-targeting and neutrophil-hitchhiking capability. The result suggests that this system can effectively hinder the formation of NETs and delay the progression of atherosclerosis.

New-generation cytopharmaceuticals with powerfully boosted extravasation for enhanced cancer therapy.

Effective extravasation of therapeutic agents into solid tumors still faces huge challenges. Since the doubted effectiveness of enhanced penetration and retention effect, first-generation neutrophil cytopharmaceuticals with encapsulated drugs have been developed to improve the drug accumulation in tumors based on the active chemotaxis and extravasation of neutrophils. Herein, a new generation of neutrophil cytopharmaceuticals with enhanced tumor-specific extravasation is reported to satisfy more complex clinical demands. This neutrophil cytopharmaceutical is obtained by anchoring vascular endothelial growth factor receptor 2 (VEGFR2)-targeting peptide K237 on neutrophil membrane after endocytosis of chemotherapeutics by neutrophils. Leveraging the cytokine-mediated active migration of neutrophils, the specific-recognition of K237 peptide to tumor vascular endothelium expedites the migration and enhances tight adhesion of neutrophils to vascular endothelium, thus improving the extravasation of therapeutic agents to target sites. Moreover, anti-angiogenesis effect from VEGFR2-blocking by K237 peptide achieves a cooperative tumor destruction with cytotoxic effects from released chemotherapeutics. This study demonstrates the great potential of enhanced proactive extravasation of cytopharmaceuticals via a cell-anchoring technology, leading to expedited drug infiltration and boosted therapeutic effects, which can be applied in other cell therapies to improve efficacy.

Reprogrammed siTNFα/neutrophil cytopharmaceuticals targeting inflamed joints for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe synovial inflammation and cartilage damage. Despite great progress in RA therapy, there still lacks the drugs to completely cure RA patients. Herein, we propose a reprogrammed neutrophil cytopharmaceuticals loading with TNFα-targeting-siRNA (siTNFα) as an alternative anti-inflammatory approach for RA treatment. The loaded siTNFα act as not only the gene therapeutics to inhibit TNFα production by macrophages in inflamed synovium, but also the editors to reprogram neutrophils to anti-inflammatory phenotypes. Leveraging the active tendency of neutrophils to inflammation, the reprogrammed siTNFα/neutrophil cytopharmaceuticals (siTNFα/TP/NEs) can rapidly migrate to the inflamed synovium, transfer the loaded siTNFα to macrophages followed by the significant reduction of TNFα expression, and circumvent the pro-inflammatory activity of neutrophils, thus leading to the alleviated synovial inflammation and improved cartilage protection. Our work provides a promising cytopharmaceutical for RA treatment, and puts forward a living neutrophil-based gene delivery platform.

Real-time detection of T cell activation by visualizing TCR nanoclusters with a cholesterol derived aggregation-induced emission probe.

Successful T-cell based immunotherapy usually depends on the activation of T cells. Most of commonly used methods for assessing T cell activity rely on the antibody-based technology, which focus on detecting protein-centered activation markers, including CD25, cytokines and so on. However, these methods always involve tedious sample-preparation process, labor-consuming and costly, which could not be utilized in real-time detection. The T cell receptor (TCR) clustering is another kind of essential T cell activation marker on the membrane, which increases during the activation state of T cells. We herein developed a cholesterol derived aggregation-induced emission (AIE) fluorescent probe (R-TPE-PEG-Chol) for detecting T cell activation in real-time. Five probes were first designed and synthesized and among them COOH-TPE-PEG-Chol displayed the best imaging effects, which had no significant impact on the key physiological functions of T cells. In addition, we have proved that COOH-TPE-PEG-Chol was introduced onto the naïve T cell membrane in its molecularly dissolved form without fluorescent emission. While during T cell activation, the formation of TCR nanoclusters would induce aggregation of membrane cholesterol, which could provoke the fluorescence signal of the COOH-TPE-PEG-Chol due to the AIE characteristic. Moreover, the enhancement of the fluorescence intensity was positively related to the activation state of T cells. Our study demonstrated the concept of cholesterol-derived AIE fluorescent probes for deciphering the spatiotemporal arrangements of TCR on the membrane during T cell activation, and consequently provided a novel and complementary strategy for detecting T cell activation in real-time.

Sensitizing Tumors to Immune Checkpoint Blockage via STING Agonists Delivered by Tumor-Penetrating Neutrophil Cytopharmaceuticals.

Immune checkpoint inhibitors (ICIs) have displayed potential efficacy in triple-negative breast cancer (TNBC) treatment, while only a minority of patients benefit from ICI therapy currently. Although activation of the innate immune stimulator of interferon genes (STING) pathway potentiates antitumor immunity and thus sensitizes tumors to ICIs, the efficient tumor penetration of STING agonists remains critically challenging. Herein, we prepare a tumor-penetrating neotype neutrophil cytopharmaceutical (NEs@STING-Mal-NP) with liposomal STING agonists conjugating on the surface of neutrophils, which is different from the typical neutrophil cytopharmaceutical that loads drugs inside the neutrophils. We show NEs@STING-Mal-NP that inherit the merits of neutrophils including proactive tumor vascular extravasation and tissue penetration significantly boost the tumor penetration of STING agonists. Moreover, the backpacked liposomal STING agonists can be released in response to hyaluronidase rich in the tumor environment, leading to enhanced uptake by tumor-infiltrating immune cells and tumor cells. Thus, NEs@STING-Mal-NP effectively activate the STING pathway and reinvigorate the tumor environment through converting macrophages and neutrophils to antitumor phenotypes, promoting the maturation of dendritic cells, and enhancing the infiltration and tumoricidal ability of T cells. Specifically, this cytopharmaceutical displays a significant inhibition on tumor growth and prolongs the survival of TNBC-bearing mice when combined with ICIs. We demonstrate that neutrophils serve as promising vehicles for delivering STING agonists throughout solid tumors and the developed neutrophil cytopharmaceuticals with backpacked STING agonists exhibit huge potential in boosting the immunotherapy of ICIs.

Single-component lipid nanoparticles for engineering SOCS1 gene-silenced dendritic cells to boost tumor immunotherapy.

Dendritic cells (DCs) that can prime antitumor responses show great potential in tumor immunotherapy, whereas the unsatisfactory effect which can be ascribed in part to the high expression of inhibitory cytokines, such as the suppressor of cytokine signaling 1 (SOCS1), restricts their application. Thus, silencing these genes in DCs is essential for DC-based therapy. However, safe and effective delivery of siRNA to DCs still faces challenges. Herein, we designed single-component lipid nanoparticles comprising a solely cationic lipid (OA2) for introducing siRNA into mouse DCs in order to inhibit the immunosuppressive gene and boost the effector responses of DC-based therapy. Compared to other multi-component lipid nanoparticles, single-component lipid nanoparticles are theoretically easy-to-control and detective, which is beneficial for future translation. We showed that the application of OA2 lipid nanoparticles significantly downregulated the expression of SOCS1 in DCs over 50%, compared with the commercial lipofectine2000. Besides, the treatment of OA2 lipid nanoparticles had no influence on the antigen capture of DCs. Thus, we fabricated a SOCS1-downregulated DC vaccine pulsed with Ova antigen and demonstrated that the antigen presentation and pro-inflammatory factor secretion ability of DCs were improved due to the SOCS1 downregulation, leading to an ameliorated immunosuppressive tumor microenvironment and finally exhibiting potent tumor prevention and suppression in B16-Ova tumor-bearing mice. Single-component lipid nanoparticles, which provide an available vector platform for siRNA delivery to primary DCs, appear to be a potent tool to engineer DCs and in turn boost DC-based tumor immunotherapy.

The Impaired Mechanism and Facilitated Therapies of Efferocytosis in Atherosclerosis.

ABSTRACT: Cardiovascular disease is responsible for the largest number of deaths worldwide, and atherosclerosis is the primary cause. Apoptotic cell accumulation in atherosclerotic plaques leads to necrotic core formation and plaque rupture. Emerging findings show that the progression of atherosclerosis appears to suppress the elimination of apoptotic cells. Mechanistically, the reduced edibility of apoptotic cells, insufficient phagocytic capacity of phagocytes, downregulation of bridging molecules, and dysfunction in the polarization of macrophages lead to impaired efferocytosis in atherosclerotic plaques. This review focuses on the characteristics of efferocytosis in plaques and the therapeutic strategies aimed at promoting efferocytosis in atherosclerosis, which would provide novel insights for the development of antiatherosclerotic drugs based on efferocytosis.

An EPR-Independent extravasation Strategy: Deformable leukocytes as vehicles for improved solid tumor therapy.

Effective delivery of therapeutic modality throughout the tumorous nidus plays a crucial role in successful solid tumor treatment. However, conventional nanomedicines based on enhanced permeability and retention (EPR) effect have yielded limited delivery/therapeutic efficiency, due mainly to the heterogeneity of the solid tumor. Leukocytes, which could intrinsically migrate across the vessel wall and crawl through tissue interstitium in a self-deformable manner, have currently emerged as an alternative drug delivery vehicle. In this review, we start with the intrinsic properties of leukocytes (e.g., extravasation and crawling inside tumor), focusing on unveiling the conceptual rationality of leveraging leukocytes as EPR-independent delivery vehicles. Then we discussed various cargoes-loading/unloading strategies for leukocyte-based vehicles as well as their promising applications. This review aims to serve as an up-to-date compilation, which might provide inspiration for scientists in the field of drug delivery.

Targeted downregulation of HIF-1α for restraining circulating tumor microemboli mediated metastasis.

Tumor metastasis is directly correlated to poor prognosis and high mortality. Circulating tumor cells (CTCs) play a pivotal role in metastatic cascades, of which CTC clusters is highly metastatic compared to single CTCs. Although platelets and neutrophils within the bloodstream could further exacerbate the pro-metastatic effect of single CTCs, the influence of platelets and neutrophils on CTC clusters mediated metastasis remains unclear. In this study, a pro-metastatic complex composed of CTC clusters, platelets and neutrophils, namely circulating tumor microemboli (CTM), was identified in vivo among different metastatic tumor, which was demonstrated with highly upregulation of hypoxia-inducible factor-1α (HIF-1α). While knock-out of HIF-1α or therapeutically downregulating of HIF-1α via HIF-1α inhibitor (BAY87-2243)-loaded neutrophil cyto-pharmaceuticals (PNEs) could efficiently restrain CTM mediated lung metastasis. The underlying mechanism of metastasis inhibition was attributed to the downregulation of HIF-1α-associated PD-L1, which would enhance immune response for inhibiting metastatic cells. Thus, our work here illustrates that hypoxia was an essential factor in promoting CTM colonization in lung. More importantly, we provide a promising strategy by targeted downregulation of HIF-1α in CTM via neutrophil cyto-pharmaceuticals for treatment of CTM mediated metastasis.

Neutrophil Cyto-Pharmaceuticals Suppressing Tumor Metastasis via Inhibiting Hypoxia-Inducible Factor-1α in Circulating Breast Cancer Cells.

Circulating tumor cells (CTCs) are reported as the precursor of tumor metastases, implying that stifling CTCs would be beneficial for metastasis prevention. However, challenges remain for the application of therapies that aim at CTCs due to lack of effective CTC-targeting strategy and sensitive therapeutic agents. Herein, a general CTC-intervention strategy based on neutrophil cyto-pharmaceuticals is proposed for suppressing CTC colonization and metastasis formation. Breast cancer 4T1 cells are infused as the mimic CTCs, and 4T1 cells trapped are first elucidated in neutrophil extracellular traps (NETs) expressing high levels of hypoxia-inducible factor-1α (HIF-1α) due to NET formation and thus promoting tumor cell colonization through enhanced migration, invasion and stemness. After verifying HIF-1α as a potential target for metastasis prevention, living neutrophil cyto-pharmaceuticals (CytPNEs) loaded with HIF-1α inhibitor are fabricated to therapeutically inhibit HIF-1α. It is demonstrated that CytPNEs can specially convey the HIF-1α inhibitor to 4T1 cells according to the inflammatory chemotaxis of neutrophils and down-regulate HIF-1α, thereby inhibiting metastasis and prolonging the median survival of mice bearing breast cancer lung metastasis. The research offers a new perspective for understanding the mechanism of CTC colonization, and puts forward the strategy of targeted intervention of CTCs as a meaningful treatment for tumor metastasis.

Poly-ß-cyclodextrin Supramolecular Nanoassembly with a pH-Sensitive Switch Removing Lysosomal Cholesterol Crystals for Antiatherosclerosis.

Cholesterol crystals (CCs), originally accumulating in the lysosome of cholesterol-laden cells, can aggravate the progression of atherosclerosis. ß-cyclodextrin (CD) is a potent cholesterol acceptor or CC solubilizer. However, the random extraction of cholesterol impedes the in vivo application of CD for removing lysosomal CCs. Here, we exploit poly-ß-cyclodextrin (pCD) as a lysosomal CC solubilizer and dextran sulfate grafted with benzimidazole (BM) as a pH-sensitive switch (pBM) to self-assemble into a supramolecular nanoassembly (pCD/pBM-SNA). The CD cavity in pCD/pBM-SNA can be efficiently sealed by hydrophobic BM at pH 7.4 (OFF). After it enters the lysosome, pCD/pBM-SNA disassembles, recovers the CD cavity to dissolve CCs into free cholesterol due to the protonation of BM (ON), and reduces CCs, finally enhancing the cholesterol efflux and promoting atherosclerosis regression. Our findings provide an "OFF-ON" tactic to remove lysosomal CCs for antiatherosclerosis as well as other diseases such as Niemann-Pick type C diseases with excessive cholesterol accumulation in the lysosome.

A neutrophil-mimetic magnetic nanoprobe for molecular magnetic resonance imaging of stroke-induced neuroinflammation.

Neuroinflammation plays a key role in the progression of brain injury induced by stroke, and has become a promising target for therapeutic intervention for stroke. Monitoring this pivotal process of neuroinflammation is highly desirable to guide specific therapy. However, there is still a lack of a satisfactory nanoprobe to selectively monitor neuroinflammation. As endothelial cell activation is a hallmark of neuroinflammation, it would be clinically relevant to develop a non-invasive in vivo imaging technique to detect the endothelial activation process. Herein, inspired by the specific neutrophil-endothelium interaction, we designed neutrophil-camouflaged magnetic nanoprobes (NMNPs) that can be used to target activated endothelial cells for improved neuroinflammation imaging. NMNPs are composed of an inner core of superparamagnetic iron oxide (SPIO)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles and a biomimetic outer shell of a neutrophil membrane, which maintained the biocompatibility and targeting ability of neutrophils and the excellent contrast effects of SPIO. Moreover, we demonstrated that NMNPs can successfully bind to inflamed cerebral vasculature using the intravital imaging of live cerebral microvessels in transient middle cerebral artery occlusion (tMCAO) mice. After that, NMNPs could further accumulate in the brain vasculature and exhibit excellent contrast effects for stroke-induced neuroinflammation and biosafety. We believe that the neutrophil-camouflaged magnetic nanoprobe could serve as a highly safe and selective nanoprobe for neuroinflammation imaging and has alluring prospects for clinical application.

Modular synthesis of amphiphilic chitosan derivatives based on copper-free click reaction for drug delivery.

Amphiphilic chitosan derivatives have attracted wide attention as drug carriers due to their physicochemical properties. However, obtaining a desired amphiphilic chitosan derivative by tuning the various functional groups was complex and time-consuming. Therefore, a facile and common synthesis strategy would be promising. In this study, a modular strategy based on strain-promoted azide-alkyne cycloaddition (SPAAC) click reaction was designed and applied in synthesizing deoxycholic acid- or octanoic acid-modified N-azido propionyl-N,O-sulfate chitosan through tuning the hydrophobic groups. Additionally, chitosan derivatives with the same substitute groups were prepared via amide coupling as controls. We demonstrated that these derivates via the two strategies showed no obvious difference in physicochemical properties, drug loading ability and biosafety, indicating the feasibility of modular strategy. Notably, the modular strategy exhibited advantages including high reactivity, flexibility and reproducibility. We believe that this modular strategy could provide varied chitosan derivatives in an easy and high-efficiency way for improving multifunctional drug carriers.

Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy.

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.

Anisamide-functionalized pH-responsive amphiphilic chitosan-based paclitaxel micelles for sigma-1 receptor targeted prostate cancer treatment.

Controlled release and tumor-selective distribution are highly desirable for anticancer nanomedicines. Here, we design and synthesize an anisamide-conjugated N-octyl-N,O-maleoyl-O-phosphoryl chitosan (a-OMPC) which can form amphiphilic micelles featuring pH-responsive release and high affinity to sigma-1 receptor-overexpressed tumors for paclitaxel (PTX) delivery. Thereinto, maleoyl and phosphoryl groups cooperatively contribute to pH-responsive drug release due to a conversion from hydrophile to hydrophobe in the acidic microenvironment of endo/lysosomes. We demonstrated that PTX-loaded a-OMPC micelles (PTX-aM) enhanced the cellular internalization via the affinity between anisamide and sigma-1 receptor, rapidly released drug in endo/lysosomes and elevated the cytotoxicity against PC-3 cells. The in vivo studies further verified that PTX-aM could largely accumulate at the tumor site even after 24 h of administration, resulting in obvious inhibition effect and prolonged survival period in PC-3 tumor xenograft-bearing mice. Moreover, OMPC showed no obvious hemolytic and acute toxicity. Collectively, this chitosan derivate holds a promising potential in application of prostate cancer-targeted drug delivery system.

An apoptotic body-biomimic liposome in situ upregulates anti-inflammatory macrophages for stabilization of atherosclerotic plaques.

The macrophages mediated inflammation participates in every stage of atherosclerosis. Attenuation of macrophages inflammatory responses by active ingredients in atherosclerotic plaques is benefit to atherosclerotic stabilization and regression, but meanwhile, it is highly desired to develop accurate therapeutics for reducing off-target effects. Previous studies revealed that the apoptotic bodies are effectively recognized and engulfed by macrophages own to increased exposure of phosphatidylserine (PtdSer), which is regarded as a key "eat-me" signal. To achieve optimal delivery efficiency, an apoptotic body biomimic liposome (AP-Lipo) is constructed by decorating PtdSer and DSPE-PEG2000-cRGDfK onto the surface of liposome for selectively delivering pioglitazone (PIO), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, into atherosclerotic macrophages while minimizing its side effects. Compared with unmodified liposome, AP-Lipo is more effective to recognize and penetrate the activated vascular endothelial monolayer, target pro-inflammatory macrophages and suppress the inflammation by upreglation of anti-inflammatory cytokines in vitro. Moreover, AP-Lipo can effectively target to atherosclerotic plaques and imped the progression of atherosclerosis by upregulating anti-inflammatory macrophages number and stabilizing the atherosclerotic plaques. In summary, this design imitates the characteristic of apoptotic body and provides a potential drug delivery system for atherosclerosis and other diseases, which attribute to inflammation mediated by macrophages.