Biomimetic Nanomaterials for the Immunomodulation of the Cardiosplenic Axis Postmyocardial Infarction.

The spleen is an important mediator of both adaptive and innate immunity. As such, attempts to modulate the immune response provided by the spleen may be conducive to improved outcomes for numerous diseases throughout the body. Here, biomimicry is used to rationally design nanomaterials capable of splenic retention and immunomodulation for the treatment of disease in a distant organ, the postinfarct heart. Engineered senescent erythrocyte-derived nanotheranostic (eSENTs) are generated, demonstrating significant uptake by the immune cells of the spleen including T and B cells, as well as monocytes and macrophages. When loaded with suberoylanilide hydroxamic acid (SAHA), the nanoagents exhibit a potent therapeutic effect, reducing infarct size by 14% at 72 h postmyocardial infarction when given as a single intravenous dose 2 h after injury. These results are supportive of the hypothesis that RBC-derived biomimicry may provide new approaches for the targeted modulation of the pathological processes involved in myocardial infarction, thus further experiments to decisively confirm the mechanisms of action are currently underway. This novel concept may have far-reaching applicability for the treatment of a number of both acute and chronic conditions where the immune responses are either stimulated or suppressed by the splenic (auto)immune milieu.

Ultrasound-Guided Microbubble-Mediated Locoregional Delivery of Multiple MicroRNAs Improves Chemotherapy in Hepatocellular Carcinoma.

Rationale: To assess treatment effects of 4 complementary miRNAs (miRNA-100/miRNA-122/antimiRNA-10b/antimiRNA-21) encapsulated in a biodegradable PLGA-PEG nanoparticle, administered by an ultrasound-guided microbubble-mediated targeted delivery (UGMMTD) approach in mouse models of hepatocellular carcinoma (HCC). Methods:In vitro apoptotic index was measured in HepG2 and Hepa1-6 HCC cells treated with various combinations of the 4 miRNAs with doxorubicin. Three promising combinations were further tested in vivo by using UGMMTD. 63 HepG2 xenografts in mice were randomized into: group 1, miRNA-122/antimiRNA-10b/antimiRNA-21/US/doxorubicin; group 2, miRNA-100/miRNA-122/antimiRNA-10b/antimiRNA-21/US/doxorubicin; group 3, miRNA-100/miRNA-122/antimiRNA-10b/US/doxorubicin; group 4, miRNA-122/anitmiRNA-10b/antimiRNA-21/doxorubicin; group 5, miRNA-100/miRNA-122/antimiRNA-10b/antimiRNA-21/doxorubicin; group 6, miRNA-100/miRNA-122/antimiRNA-10b/doxorubicin; group 7, doxorubicin only treatment; and group 8, without any treatment. Tumor volumes were measured through 18 days. H&E staining, TUNEL assay, and qRT-PCR quantification for delivered miRNAs were performed. Results:In vivo results showed that UGMMTD of miRNAs with doxorubicin in groups 1-3 significantly (P<0.05) delayed tumor growth compared to control without any treatment, and doxorubicin only from day 7 to 18. On qRT-PCR, levels of delivered miRNAs were significantly (P<0.05) higher in groups 1-3 upon UGMMTD treatment compared to controls. TUNEL assay showed that upon UGMMTD, significantly higher levels of apoptotic cell populations were observed in groups 1-3 compared to controls. Toxicity was not observed in various organs of different groups. Conclusions: UGMMTD of miRNA-100/miRNA-122/antimiRNA-10b/antimiRNA-21 combination improved therapeutic outcome of doxorubicin chemotherapy in mouse models of HCC by substantial inhibition of tumor growth and significant increase in apoptotic index.

Engineered Cell-Derived Vesicles Displaying Targeting Peptide and Functionalized with Nanocarriers for Therapeutic microRNA Delivery to Triple-Negative Breast Cancer in Mice.

Polymeric nanocarriers (PNCs) can be used to deliver therapeutic microRNAs (miRNAs) to solid cancers. However, the ability of these nanocarriers to specifically target tumors remains a challenge. Alternatively, extracellular vesicles (EVs) derived from tumor cells show homotypic affinity to parent cells, but loading sufficient amounts of miRNAs into EVs is difficult. Here, it is investigated whether uPAR-targeted delivery of nanococktails containing PNCs loaded with therapeutic antimiRNAs, and coated with uPA engineered extracellular vesicles (uPA-eEVs) can elicit synergistic antitumor responses. The uPA-eEVs coating on PNCs increases natural tumor targeting affinities, thereby enhancing the antitumor activity of antimiRNA nanococktails. The systemic administration of uPA-eEV-PNCs nanococktail shows a robust tumor tropism, which significantly enhances the combinational antitumor effects of antimiRNA-21 and antimiRNA-10b, and leads to significant tumor regression and extension of progression free survival for syngeneic 4T1 tumor-bearing mice. In addition, the uPA-eEV-PNCs-antimiRNAs nanococktail plus low dose doxorubicin results in a synergistic antitumor effect as evidenced by inhibition of tumor growth, reduction of lung metastases, and extension of survival of 4T1 tumor-bearing mice. The targeted combinational nanococktail strategy could be readily translated to the clinical setting by using autologous cancer cells that have flexibility for ex vivo expansion and genetic engineering.

Bio-inspired nanomaterials as novel options for the treatment of cardiovascular disease.

Cardiovascular disease (CVD) and its sequelae have long been the leading causes of death and disability in the developed world. Although mortality associated with CVD has been decreasing, due in large part to novel therapeutic options, the rate of decrease has flattened. Thus, there is a great need to investigate alternate therapeutic strategies that can increase efficacy while decreasing adverse effects. Nanomaterials have been widely investigated and have emerged as promising tools for both therapeutic and diagnostic purposes in oncology; however, the potential of nanomaterials has not been extensively explored for cardiovascular medicine. In this review, we focus on recent developments in the field of nanomedicines targeted for CVDs, with a special emphasis on cell membrane-coated nanoparticles (NPs) and their applications.

Biomimetic bacterial and viral-based nanovesicles for drug delivery, theranostics, and vaccine applications.

Smart nanocarriers obtained from bacteria and viruses offer excellent biomimetic properties which has led to significant research into the creation of advanced biomimetic materials. Their versatile biomimicry has application as biosensors, biomedical scaffolds, immobilization, diagnostics, and targeted or personalized treatments. The inherent natural traits of biomimetic and bioinspired bacteria- and virus-derived nanovesicles show potential for their use in clinical vaccines and novel therapeutic drug delivery systems. The past few decades have seen significant progress in the bioengineering of bacteria and viruses to manipulate and enhance their therapeutic benefits. From a pharmaceutical perspective, biomimetics enable the safe integration of naturally occurring bacteria and virus particles to achieve high, stable rates of cellular transfection/infection and prolonged circulation times. In addition, biomimetic technologies can overcome safety concerns associated with live-attenuated and inactivated whole bacteria or viruses. In this review, we provide an update on the utilization of bacterial and viral particles as drug delivery systems, theranostic carriers, and vaccine/immunomodulation modalities.

Labeling and tracking cells with gold nanoparticles.

Gold nanoparticles (AuNPs) have garnered much attention as contrast agents for computerized tomography (CT) because of their facile synthesis and surface functionalization, in addition to their significant X-ray attenuation and minimal cytotoxicity. Cell labeling using AuNPs and tracking of the labeled cells using CT has become a time-efficient and cost-effective method. Actively targeted AuNPs can enhance CT contrast and sensitivity, and further reduce the radiation dosage needed during CT imaging. In this review, we summarize the state-of-the-art use of AuNPs in CT for cell tracking, including the precautionary steps necessary for their use and the difficulty in translating the process into clinical use.

Current potential and challenges in the advances of liquid crystalline nanoparticles as drug delivery systems.

Lyotropic nonlamellar liquid crystalline nanoparticles (NPs) (LCN), such as cubosomes and hexosomes, are useful tools for applications in drug delivery because of their unique structural properties. LCNs are highly versatile carriers that can be applied for use with topical, oral, and intravenous treatments. In recent years, significant research has focused on improving their preparation and characterization, including controlling drug release and enhancing the efficacy of loaded bioactive molecules. Nevertheless, the clinical translation of LCN-based carriers has been slow. In this review, we highlight recent advances and challenges in the development and application of LCN, providing examples of their topical, oral, and intravenous drug delivery applications, and discussing translational obstacles to LCN as a NP technology.

Molecular Imaging of Retinoic Acids in Live Cells Using Single-Chain Bioluminescence Probes.

Retinoic acid (RA) is a key metabolite necessary for embryonic development and differentiation in vertebrates. We demonstrate the utility of genetically encoded, ligand-activatable single-chain bioluminescence probes for detecting RAs from different biological sources. We examined 13 different molecular designs to identify an efficient single-chain probe that can quantify RA with significant sensitivity. The optimal probe consisted of four components: the N- and C-terminal fragments of artificial luciferase variant-16 (ALuc16), the ligand binding domain of retinoic acid receptor α (RARα LBD), and an LXXLL interaction motif. This probe showed a 5.2-fold greater bioluminescence intensity in response to RA when compared to the vehicle control in live mammalian cells. The probe was highly selective to all-trans-RA (at-RA), and highly sensitive in determining at-RA levels in cells derived from tumor xenografts created using MDA-MB-231 cells engineered to stably express the probe. We also detected RA levels in serum and cerebrospinal fluid. Using this probe, the detection limit for at-RA was ∼10-9.5 M, with a linear range of two orders. We present a highly useful technique to quantitatively image endogenous at-RA levels in live mammalian cells expressing novel single-chain bioluminescence probes.

Biodegradable polymers for modern vaccine development.

Most traditional vaccines are composed either of a whole pathogen or its parts; these vaccines, however, are not always effective and can even be harmful. As such, additional agents known as adjuvants are necessary to increase vaccine safety and efficacy. This review summarizes the potential of biodegradable materials, including synthetic and natural polymers, for vaccine delivery. These materials are highly biocompatible and have minimal toxicity, and most biomaterial-based vaccines delivering antigens or adjuvants have been shown to improve immune response, compared to formulations consisting of the antigen alone. Therefore, these materials can be applied in modern vaccine development.

Cell membrane-coated nanocarriers: the emerging targeted delivery system for cancer theranostics.

Cancer is a leading cause of death worldwide. The use of nanocarriers (NCs) has generated significant interest to improve cancer therapy by targeted delivery. However, conventional NCs in general lack specificity and have poor biodistribution, resulting in low efficacy in cancer therapy. To circumvent this problem, there has been an increasing focus on cancer cell membrane-coated NCs (CCMCNCs), which can deliver therapeutics directly to tumor cells. CCMCNCs comprise active cancer cell surface adhesive molecules combined with other functional proteins, and offer extended blood circulation with robust cell-specific targeting, ensuring enhanced intratumoral penetration and higher tumor-specific accumulation of NCs. In this review, we discuss the preparation, homologous targeting mechanisms, and application of CCMCNCs in targeted cancer therapy.

Bioengineered stem cell membrane functionalized nanocarriers for therapeutic targeting of severe hindlimb ischemia.

Bioengineering strategies to enhance the natural targeting function of nanocarriers would expand their therapeutic applications. Here, we designed bioengineered stem cell membrane-functionalized nanocarriers (BSMNCs) harboring C-X-C chemokine receptor type 4 (CXCR4) to achieve robust targeting and also to increase their retention time in ischemic tissue. Stem cell membrane coated nanocarrier (SMNCs) or poly (lactic-co-glycolic acid) (PLGA) nanocarriers (PNCs) and BSMNCs were prepared by functionalizing PNCs with human adipose-derived stem cells (hASCs) membranes and hASCs engineered to overexpress CXCR4-receptor, respectively. The functionalization of PNCs with stem cell membranes derived from hASCs significantly enhance the nanocarrier penetration across endothelial cell barrier compare to PNCs. In addition, stem cell membrane functionalization on PNCs also significantly decreased the nanoparticles uptake in J774 (murine) and THP (human) macrophages respectively from 84% to 76%-29% and 24%. Interestingly, BSMNCs showed much higher level of accumulation in ischemic tissue than SMNCs. Systemic retro-orbital injection of BSMNCs loaded with VEGF into mice with hindlimb ischemia resulted substantially enhancement of blood reperfusion, muscle repair, and limb salvage compared to animals treated with SMNCs loaded with similar concentration of VEGF. The reported strategy could be used to create biocompatible and custom-tailored biomimetic nanoparticles with various hybrid functionalities, which may overcome the limitations of current nanoparticle-based therapeutic and imaging platforms.

Lipid-based surface engineering of PLGA nanoparticles for drug and gene delivery applications.

The use of poly(lactic-co-glycolic acid) (PLGA)-based nanocarriers presents several major challenges, including their synthetic hydrophobic surface, low transfection efficiency, short circulation half-life, and nonspecific tissue distribution. Numerous engineering strategies have been employed to overcome these problems, with lipid-based surface functionalization of PLGA nanoparticles (NPs) showing promising results in the development of PLGA-based clinical nanomedicines. Surface engineering with different lipids enhances the target specificity of the carrier and improves its physicochemical properties as well as NP-cell associations, such as cellular membrane permeability, immune responses, and long circulation half-life in vivo. This review focuses on recent advances in the lipid-based surface engineering of PLGA NPs for drug and gene delivery applications.