Synthetic Vehicles Research Articles

Harnessing exosomes for targeted therapy: strategy and application.

Exosomes, nanoscopic extracellular vesicles produced by cells, are pivotal in mediating intracellular communication by transporting nucleic acids, proteins, lipids, and other bioactive molecules, thereby influencing physiological and pathological states. Their endogenous origin and inherent diversity confer distinct advantages over synthetic vehicles like liposomes and nanoparticles in diagnostic and therapeutic applications. Despite their potential, the clinical utility of exosomes is hampered by challenges such as limited storage stability, yield, purity, and targeting efficiency. This review focuses on exosomes as targeted therapeutic agents, examining their biogenesis, classification, isolation, and characterisation, while also addressing the current limitations in yield, purity, and targeting. We delve into the literature to propose optimisation strategies that can enhance their therapeutic efficacy and accelerate the translation of exosome-based therapies into clinical practice.

Extracellular Vesicles as New Players in Drug Delivery: A Focus on Red Blood Cells-Derived EVs.

The article is divided into several sections, focusing on extracellular vesicles' (EVs) nature, features, commonly employed methodologies and strategies for their isolation/preparation, and their characterization/visualization. This work aims to give an overview of advances in EVs' extensive nanomedical-drug delivery applications. Furthermore, considerations for EVs translation to clinical application are summarized here, before focusing the review on a special kind of extracellular vesicles, the ones derived from red blood cells (RBCEVs). Generally, employing EVs as drug carriers means managing entities with advantageous properties over synthetic vehicles or nanoparticles. Besides the fact that certain EVs also reveal intrinsic therapeutic characteristics, in regenerative medicine, EVs nanosize, lipidomic and proteomic profiles enable them to pass biologic barriers and display cell/tissue tropisms; indeed, EVs engineering can further optimize their organ targeting. In the second part of the review, we focus our attention on RBCEVs. First, we describe the biogenesis and composition of those naturally produced by red blood cells (RBCs) under physiological and pathological conditions. Afterwards, we discuss the current procedures to isolate and/or produce RBCEVs in the lab and to load a specific cargo for therapeutic exploitation. Finally, we disclose the most recent applications of RBCEVs at the in vitro and preclinical research level and their potential industrial exploitation. In conclusion, RBCEVs can be, in the near future, a very promising and versatile platform for several clinical applications and pharmaceutical exploitations.

Design of simulation-based pilot training systems using machine learning agents

AbstractThe high operational cost of aircraft, limited availability of air space, and strict safety regulations make training of fighter pilots increasingly challenging. By integrating Live, Virtual, and Constructive simulation resources, efficiency and effectiveness can be improved. In particular, if constructive simulations, which provide synthetic agents operating synthetic vehicles, were used to a higher degree, complex training scenarios could be realised at low cost, the need for support personnel could be reduced, and training availability could be improved. In this work, inspired by the recent improvements of techniques for artificial intelligence, we take a user perspective and investigate how intelligent, learning agents could help build future training systems. Through a domain analysis, a user study, and practical experiments, we identify important agent capabilities and characteristics, and then discuss design approaches and solution concepts for training systems to utilise learning agents for improved training value.

Engineering the Immune Adaptor Protein STING as a Functional Carrier

AbstractActivation of the stimulator of interferon genes (STING) pathway through cyclic dinucleotides (CDNs) is being explored as potent vaccine adjuvants against infectious diseases and to increase tumor immunogenicity toward cancer immunotherapy. To date, a myriad of synthetic vehicles, including liposomes, polymers, and other nanoparticle platforms, have been developed to improve the bioavailability and therapeutic efficacy of STING agonists in preclinical mouse models. Compared to synthetic materials, protein‐based carriers represent an attractive delivery platform owing to their biocompatibility, amenability to genetic engineering, and intrinsic capacity to form well‐defined structures. Here, the immune adaptor STING is engineered as aprotein‐based delivery system for efficient encapsulation and intracellular delivery of CDNs. Through genetic fusion with a protein transduction domain, the recombinant STING can spontaneously penetrate cells to markedly enhance the delivery of CDNs in a mouse vaccination model and a syngeneic melanoma model. As certain tumor cells can evade immune surveillance via loss of STING expression, authors further unveiled that the STING platform can serve as a functional vehicle to restore the STING signaling in cell lines with impaired STING expression. Altogether, their delivery platform may offer a unique direction toward targeting STING‐silenced tumors and augmenting the efficacy of STING‐based vaccine adjuvants.

Hybrid Cell Membrane-Camouflaged Nanoparticle: A Novel Multifunctional Biomimetic Drug Delivery Carrier for Cancer Therapy

Biomimetic nanotechnology through camouflaging synthetic nanoparticles with natural cell membranes, which bestows with immune evasion and superior targeting capacity, has been extensively applied in drug delivery systems (DDS) over the last decades. Theses biomimetic nanoparticles (NPs) not only reserve the physicochemical features of the synthetic vehicles but also inherit the cell membranes' intrinsic functionalities. Combined with these benefits, optimized nano-biomimetic DDS allow maximum delivery efficacy. Compared to erythrocyte/cancer single cell membrane, the hybrid cell membranes expressing CD47 membrane protein and self-recognition molecules, from erythrocytes and cancer cells, provides incredible features to the synthetic vehicles, such as immune evasion, long-term circulation, and homotypic targeting. In this review, we described the preparation strategies, the camouflaging mechanism, and the antitumor applications of hybrid cell membrane-camouflaged nanoparticles. Moreover, we discussed further modification of the hybrid cell membranes and the surface properties of fusion cellular membranes. Finally, we summarized the primary challenges and opportunities associated with these nanoparticles.

Synthetic Vehicles for Encapsulation and Delivery of CRISPR/Cas9 Gene Editing Machinery

AbstractClustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR‐associated 9 (Cas‐9) technology holds tremendous potential as a gene editing tool. Different strategies have been adopted for in vitro and in vivo delivery of CRISPR/Cas9, including both viral and non‐viral. The possibility of tailoring properties of nanosized systems makes the molecular design of self‐assembled non‐viral delivery systems based on organic (lipids and polymers) and hybrid (zeolitic imidazolate frameworks, ZIF and gold nanoparticles) materials of a great interest in CRISPR/Cas9 delivery. This review highlights the progress and challenges of organic and hybrid CRISPR/Cas9 delivery vehicles.

Cell membrane capsules as biomimetic drug carriers

Event Abstract Back to Event Cell membrane capsules as biomimetic drug carriers Lijie Han1, Yuanhong Zhang1 and Zhengwei Mao1 1 Zhejiang University, Department of Polymer Science and Engieering, China Introduction: Systemic administration of chemotherapeutic agents results in indiscriminate drug distribution and severe toxicity. Until now, encapsulation and targeting of drugs have typically relied on synthetic vehicles, which cannot minimize clearance by the renal system and may also increase the risk of chemical side effects. Cell membrane capsules (CMCs) provide a generic and far more natural approach to the challenges of drug encapsulation and delivery in vivo[1],[2]. Results and Discussion: Here aptamer AS1411, which can recognize and bind over-expressed nucleolin on cancer cell membrane, was chemically conjugated onto CMCs. As a result, AS1411 modified CMCs showed enhanced ingestion in certain cancer cells in vitro and accumulation in mouse cancer xenografts in vivo. Chemotherapeutics and contrast agents with therapeutically significant concentrations can be packaged into CMCs by reversible permeating their plasma membranes. The systematic administration of cancer targeting CMCs loaded with doxorubicin hydrochloride can significantly inhibit tumor growth in mouse xenografts, with significantly reduced toxicity compare to free drug. These findings suggest that cancer targeting CMCs may have considerable benefits in drug delivery and cancer treatment. Conclusion: In this study, biocompatible cell membrane capsules were prepared from human endothelial cells with preserved membrane structure and functions. Cancer cell targeting aptamer AS1411 was conjugated onto the CMCs, resulted in enhanced ingestion of CMCs in certain cancer cells and accumulation of CMCs in mouse tumor xenografts. Chemotherapeutics and contrast agents can be packaged into the CMCs by reversible permeating their plasma membranes. The systematic administration of cancer targeting CMCs loaded with doxorubicin can inhibit tumor growth in mouse xenografts, with significantly reduced toxicity compare to free drug. These findings suggest that targeting CMCs may have considerable benefits in drug delivery and cancer treatment. Natural Science Foundation of China (51120135001); Key Science Technology Innovation Team of Zhejiang Province (2013TD02)

Cell Membrane Capsules for Encapsulation of Chemotherapeutic and Cancer Cell Targeting in Vivo.

Systemic administration of chemotherapeutic agents can cause indiscriminate drug distribution and severe toxicity. Until now, encapsulation and targeting of drugs have typically relied on synthetic vehicles, which cannot minimize the clearance by the renal system and may also increase the risk of chemical side effects. Cell membrane capsules (CMCs) provide a generic and far more natural approach to the challenges of drug encapsulation and delivery in vivo. Here aptamer AS1411, which can recognize and bind overexpressed nucleolin on a cancer cell membrane, was chemically conjugated onto CMCs. As a result, AS1411 modified CMCs showed enhanced ingestion in certain cancer cells in vitro and accumulation in mouse cancer xenografts in vivo. Chemotherapeutics and contrast agents with therapeutically significant concentrations can be packaged into CMCs by reversible permeating their plasma membranes. The systematic administration of cancer targeting CMCs loaded with doxorubicin hydrochloride can significantly inhibit tumor growth in mouse xenografts, with significantly reduced toxicity compared to free drug. These findings suggest that cancer targeting CMCs may have considerable benefits in drug delivery and cancer treatment.

Preparation and Mechanism Insight of Nuclear Envelope-like Polymer Vesicles for Facile Loading of Biomacromolecules and Enhanced Biocatalytic Activity

The facile loading of sensitive and fragile biomacromolecules, such as glucose oxidase, hemoglobin, and ribonucleic acid (RNA), via synthetic vehicles directly in pure aqueous media is an important technical challenge. Inspired by the nucleus pore complex that connects the cell nucleus and the cytoplasm across the nuclear envelope, here we describe the development of a kind of polymeric nuclear envelope-like vesicle (NEV) to address this problem. The NEV is tailored to form the polymer pore complex (70 nm, similar to a nucleus pore complex) within the vesicle membrane based on nanophase segregation, which is confirmed via fluorescence spectrometry and dynamic light scattering (DLS) during self-assembly. This pH-triggered polymer pore complex can mediate the transportation of biomacromolecules across the vesicle membrane. Moreover, the NEVs facilitate the natural consecutive enzyme-catalyzed reactions via the H(+) sponge effect. This simple strategy might also be extended for mimicking other synthetic cell organelles.

Emotions in robot psychology

In his famous thought experiments on synthetic vehicles, Valentino Braitenberg stipulated that simple stimulus-response reactions in an organism could evoke the appearance of complex behavior, which, to the unsuspecting human observer, may even appear to be driven by emotions such as fear, aggression, and even love (Braitenberg, Vehikel. Experimente mit künstlichen Wesen, Lit Verlag, 2004). In fact, humans appear to have a strong propensity to anthropomorphize, driven by our inherent desire for predictability that will quickly lead us to discern patterns, cause-and-effect relationships, and yes, emotions, in animated entities, be they natural or artificial. But might there be reasons, that we should intentionally "implement" emotions into artificial entities, such as robots? How would we proceed in creating robot emotions? And what, if any, are the ethical implications of creating "emotional" robots? The following article aims to shed some light on these questions with a multi-disciplinary review of recent empirical investigations into the various facets of emotions in robot psychology.

Alkyl groups as synthetic vehicles in gold-mediated oxidative coupling reactions

The use of surface-bound alkyl and phenyl groups as synthetic vehicles in coupling reactions on oxygen-activated Au(111) is demonstrated by the formation of ethers via alkyl and phenyl iodides. Ethers are formed by successive additions of surface-bound alkyl groups to adsorbed atomic oxygen to form first the alkoxy and then the ether. The addition of the ethyl group to adsorbed oxygen on Au(111) is the rate-limiting step leading to diethyl ether formation. Alkyl groups also add to adsorbed alkoxy groups formed from alcohols. An unusual feature of the alkyl iodide reactions on Au is that oxygen is not required for the activation step; hence, opening new potential reactive pathways on metallic Au.

Erythrocyte‐Inspired Delivery Systems

Herein recent progress in developing red blood cell (RBC)-inspired delivery systems is reviewed, with an emphasis on how our growing understanding of fundamental biological properties of natural RBCs has been applied in the design and engineering of these delivery systems. Specifically, progress achieved in developing carrier RBCs, a class of delivery vehicles engineered by directly loading natural RBCs with therapeutic agents, will be reviewed. Then alternative approaches to engineering synthetic vehicles through mimicking the mechanobiological and chemico-biological properties of natural RBCs will be considered. The synthesis and application of RBC membrane-derived vesicles, of which the natural RBC membranes are collected and directly utilized to prepare drug carriers, will then be discussed. Finally, a recent approach in engineering RBC membrane-camouflaged nanoparticle systems that combine advantages of natural RBCs and synthetic biomaterials will be highlighted. These developments indicate that RBC-inspired delivery systems will result in next-generation nanomedicine with extensive medical applications.

Cell- and gene-based approaches to tendon regeneration

Repair of rotator cuff tears in experimental models has been significantly improved by the use of enhanced biologic approaches, including platelet-rich plasma, bone marrow aspirate, growth factor supplements, and cell- and gene-modified cell therapy. Despite added complexity, cell-based therapies form an important part of enhanced repair, and combinations of carrier vehicles, growth factors, and implanted cells provide the best opportunity for robust repair. Bone marrow-derived mesenchymal stem cells provide a stimulus for repair in flexor tendons, but application in rotator cuff repair has not shown universally positive results. The use of scaffolds such as platelet-rich plasma, fibrin, and synthetic vehicles and the use of gene priming for stem cell differentiation and local anabolic and anti-inflammatory impact have both provided essential components for enhanced tendon and tendon-to-bone repair in rotator cuff disruption. Application of these research techniques in human rotator cuff injury has generally been limited to autologous platelet-rich plasma, bone marrow concentrate, or bone marrow aspirates combined with scaffold materials. Cultured mesenchymal progenitor therapy and gene-enhanced function have not yet reached clinical trials in humans. Research in several animal species indicates that the concept of gene-primed stem cells, particularly embryonic stem cells, combined with effective culture conditions, transduction with long-term integrating vectors carrying anabolic growth factors, and development of cells conditioned by use of RNA interference gene therapy to resist matrix metalloproteinase degradation, may constitute potential advances in rotator cuff repair. This review summarizes cell- and gene-enhanced cell research for tendon repair and provides future directions for rotator cuff repair using biologic composites.

The influence of size and charge of chitosan/polyglutamic acid hollow spheres on cellular internalization, viability and blood compatibility

Polymeric hollow spheres can be tailored as efficient carriers of various therapeutic molecules due to their tunable properties. However, the entry of these synthetic vehicles into cells, their cell viability and blood compatibility depend on their physical and chemical properties e.g. size, surface charge. Herein, we report the effect of size and surface charge on cell viability and cellular internalization behaviour and their effect on various blood components using chitosan/polyglutamic acid hollow spheres as a model system. Negatively charged chitosan/polyglutamic acid hollow spheres of various sizes 100, 300, 500 and 1000 nm were fabricated using a template based method and covalently surface modified using linear polyethylene glycol and methoxyethanol amine to create a gradient of surface charge from negative to neutrally charged spheres respectively. The results here suggest that both size and surface charge have a significant influence on the sphere’s behaviour, most prominently on haemolysis, platelet activation, plasma recalcification time, cell viability and internalization over time. Additionally, cellular internalization behaviour and viability was found to vary with different cell types. These results are in agreement with those of inorganic spheres and liposomes, and can serve as guidelines for tailoring polymeric solid spheres for specific desired applications in biological and pharmaceutical fields, including the design of nanometer to submicron-sized delivery vehicles.

Synthetic vehicles for DNA vaccination

Synthetic vehicles for DNA vaccination

Nanoparticle Albumin–Bound Paclitaxel for Metastatic Breast Cancer

The taxanes, paclitaxel and docetaxel, are among the most important drugs in the modern treatment of metastatic breast cancer. By the mid 1990s, several phase II trials had demonstrated both agents to have considerable activity in the metastatic setting. Phase III trials were then conducted to compare these agents with the then reference agent, doxorubicin. In 1999, a large randomized trial comparing docetaxel with doxorubicin found an improved response rate in patients who received docetaxel (48% v 33%; P .008), though differences in time to progression (26 v 21 weeks) and survival (15 v 14 months) were not statistically significant. A similar study that compared paclitaxel at a dose of 200 mg/m given over 3 hours, with doxorubicin 75 mg/m, showed paclitaxel to have an inferior response rate (25% v 41%; P .003) and time to progression (3.9 v 7.5 months; P .001) but again, overall survival was not statistically different between the two arms (15.6 v 18.3 months), possibly as a result of the preplanned cross-over on progression. Both agents, however, were rapidly adopted for the treatment of metastatic breast cancer, especially for the many women who had received an anthracycline in the adjuvant setting. Trials were subsequently launched to examine taxane combinations in advanced disease, and while some have demonstrated improved efficacy compared with single agents, this benefit has to be balanced against the excess toxicities seen with some of these regimens. This encouraging activity of taxanes in advanced disease led investigators to examine their role in addition to anthracyclines in the adjuvant setting. The first to be reported was CALGB (Cancer and Leukemia Group B) 9344 and the final analysis of this trial showed improvements in 5-year disease-free and overall survival with the addition of four cycles of paclitaxel to four cycles of doxorubicin cyclophosphamide (disease-free survival [DFS] 70% v 65%, P .0023; overall survival [OS] 80% v 77%, P .0064). Other paclitaxel adjuvant studies have shown less convincing benefits. Docetaxel has also been evaluated in several adjuvant trials. In the Breast Cancer International Research Group study (BCIRG 001), six cycles of doxorubicin, docetaxel, and cyclophosphamide (TAC) were found to be associated with superior DFS and OS compared with doxorubicin, fluorouracil, and cyclophosphamide (FAC; DFS 75% v 68%; P .001; OS 87% v 81%, P .008). Taxanes are now commonly used in adjuvant regimens for women with high-risk disease. Parallel to these studies, major advances have been achieved for women with HER-2–overexpressing breast cancer by employing schedules combining taxanes plus trastuzumab in advanced disease and in the adjuvant setting. Despite their widespread use, both docetaxel and paclitaxel are associated with significant toxicities, including alopecia, fatigue, myalgia, nail changes, myelosuppression, neuropathy, and hypersensitivity reactions. Although these adverse effects are manageable for the majority of patients, it has meant there are limitations on the duration of therapy and on combining the taxanes with other agents with overlapping toxicity profiles. Paclitaxel and docetaxel are highly hydrophobic, and therefore have to be delivered in synthetic vehicles. In the case of paclitaxel the vehicle is polyoxyethylated castor oil (Cremophor EL) and ethanol, whereas the combination of polysorbate 80 and ethanol are used for docetaxel. It has become increasingly recognized that the vehicles may be responsible for some of the “taxane-associated toxicity,” particularly fluid retention and hypersensitivity. The experiences from the early phase I and II trials of these drugs found that the incidence of such reactions could be reduced to acceptable levels with the use of premedication schedules containing antihistamines together with moderate to high doses of corticosteroids. It is in large part because of the toxicities associated with the current formulations of taxanes that strategies to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 31 NOVEMBER 1 2005

219. Development of a Polyethylene Glycol Gene Delivery Vehicle

The overall objective of this project is to design a novel synthetic gene therapy vehicle with a polyethylene glycol (PEG) backbone and to use this vehicle to study the barriers to gene delivery. Current cationic polymer based synthetic vehicles, such as polyethyleneimine (PEI) and poly-L-lysine (PLL), are able to successfully condense DNA, but the efficacy of these vehicles in vitro is limited. Non-specific interactions result in low circulation half-lives and stabilities in the presence of physiological salt concentrations and serum proteins. Coupling PEG to the surface of cationic polymer vehicles has shown to improve their stability in the presence of salt and serum proteins, however the transfection efficiency of the vehicles decreased 2. We hypothesize that by using a PEG backbone modified with acrylate end groups 1 for coupling of various moieties, such as a DNA binding peptide (DBP) from the B-ZIP protein 3, we can overcome these limits. In this study, particle size, zeta potential, cytotoxicity, and transfection efficiency of PEG-based vehicles was compared with PEI and PLL-based vehicles.

Basic peptides as functional components of non-viral gene transfer vehicles.

Improving the performance of non-viral gene-delivery vehicles that consist of synthetic compounds and nucleic acids is a key to successful gene therapy. Supplementing synthetic vehicles with various biological functions by using natural or artificial peptides is a promising approach with which to achieve this goal. One of the obstacles hindering this effort is that some of the potentially useful peptides, especially those with many basic amino acid residues, interfere with the formation of the complex owing to strong electrostatic interactions with the nucleic acid. In this review, we describe our recent work in examining the potential of these peptides in gene delivery, using a recombinant lambda phage particle as the model for the gene-delivery complex. Lambda phage encapsulates large duplex DNA in a rigid polyplex-like shell with a diameter of 55 nm, and can display various peptides on this capsid, independently of particle formation. By examining the expression of marker genes encapsulated in the phage capsid, we have demonstrated that the protein transduction domain of HIV Tat protein and the nuclear localization signal derived from SV40 T antigen can remarkably facilitate the delivery of these marker genes across the two major barriers, the cell membrane and the nuclear membrane, respectively. Our results indicate that these basic peptides can constitute effective components of synthetic gene-transfer complexes, as long as sufficient copies are displayed on the outer surface of the complex.

Incorporation of reversibly cross-linked polyplexes into LPDII vectors for gene delivery.

LPDII vectors are synthetic vehicles for gene delivery composed of polycation-condensed DNA complexed with anionic liposomes. In this study, we evaluated the stability and transfection properties of polyethylenimine (PEI, 25 kDa)/DNA polyplexes before and after covalent cross-linking with dithiobis(succinimidylpropionate) (DSP) or dimethyl x 3,3'-dithiobispropionimidate x 2HCl (DTBP), either alone or as a component of LPDII vectors. We found that cross-linking PEI/DNA polyplexes at molar ratios > or =10:1 (DSP or DTBP:PEI) stabilized these complexes against polyanion disruption, and that this effect was reversible by reduction with 20 mM dithioerythritol (DTE). Transfection studies with polyplexes cross-linked at molar ratios of 10:1-100:1 in KB cells, a folate receptor-positive oral carcinoma cell line, showed decreasing luciferase gene expression with increasing cross-linking ratio. Subsequently, polyplexes, cross-linked with DSP at a molar ratio of 10:1, were combined with anionic liposomes composed of diolein/cholesteryl hemisuccinate (CHEMS) (6:4 mol/mol), diolein/CHEMS/poly(ethylene glycol)-distearoylphosphatidylethanolamine (PEG-DSPE) (6:4:0.05 mol/mol), or diolein/CHEMS/folate-PEG-cholesterol (folate-PEG-Chol) (6:4:0.05 mol/mol) for LPDII formation. Transfection studies in KB cells showed that LPDII vectors containing cross-linked polyplexes mediated approximately 2-15-fold lower gene expression than LPDII prepared with un-cross-linked polyplexes, depending on the lipid:DNA ratio. Inclusion of PEG-DSPE at 0.5 mol % appeared to further decrease transfection levels approximately 2-5-fold. Compared with LPDII formulated with PEG-DSPE, LPDII incorporating 0.5 mol % folate-PEG-Chol exhibited higher luciferase activities at all lipid:DNA ratios tested, achieving an approximately 10-fold increase at a lipid:DNA ratio of 5. Compared with cross-linked LPDII vectors without PEG-DSPE, inclusion of folate-PEG-Chol increased luciferase activities 3-4-fold between lipid:DNA ratios of 1 and 5. Interestingly, inclusion of 1 mM free folate in the growth media during transfection increased transfection activity approximately 3-4-fold for cross-linked LPDII vectors and LPDII containing folate-PEG-Chol, but had no effect on the transfection activity of LPDII formulated with PEG-DSPE. However, in the presence of 5 mM free folate, the luciferase activity mediated by LPDII vectors containing folate-PEG-Chol was reduced approximately 6-fold. Transmission electron micrographs were also obtained to provide evidence of LPDII complex formation. Results showed that cross-linked LPDII vectors appear as roughly spherical aggregated complexes with a rather broad size distribution ranging between 300 and 800 nm.

Engineering the surface properties of synthetic gene delivery vectors.

Synthetic gene delivery vehicles are a highly promising approach to gene delivery; however, several problems must still be overcome before they can begin to enjoy dinical success. A number of these problems can be addressed by engineering and optimizing the properties of the vector surface, the component of the particle that interacts and "communicates" with tissues and cells during the delivery process. Surfaces must be engineered to satisfy two ostensibly conflicting constraints: the ability to interact specifically with a target cell while avoiding nonspecific protein interactions, particularly with components of the immune system. We summarize progress that has been made in both these areas and discuss several approaches where the intersection of biological and chemical solutions promises to significantly advance the engineering of synthetic vehicles.