Review Macromolecular Bioscience wileyonlinelibrary.com © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim (1 of 16) 1600361 DOI: 10.1002/mabi.201600361 The goal of drug delivery is to deliver therapeutics to the site of disease while reducing unwanted side effects. In recent years, a diverse variety of synthetic nano and microparticles have been developed as drug delivery systems. The success of these systems for drug delivery lies in their ability to overcome biological barriers such as the blood–brain barrier, to evade immune clearance and avoid nonspecific biodistribution. This Review provides an overview of recent advances in the design of biohybrid drug delivery systems, which combine cells with synthetic systems to overcome some of these biological hurdles. Examples include eukaryotic cells, such as stem cells, red blood cells, immune cells, platelets, and cancer cells that are used to carry drug-loaded synthetic particles. Synthetic particles can also be cloaked with naturally derived cell membranes and thereby evade immune clearance, exhibit prolonged systemic circulation, and target specific tissues by capitalizing on the interaction/homing tendency of certain cells and their membrane components to particular tissues. Different designs of cell-based bio- hybrid systems and their applica- tions, as well as their promise and limitations, are discussed herein. Cell-Based Biohybrid Drug Delivery Systems: The Best of the Synthetic and Natural Worlds Samagya Banskota, Parisa Yousefpour, Ashutosh Chilkoti* S. Banskota, [†] P. Yousefpour, [†] Prof. A. Chilkoti Department of Biomedical Engineering Duke University Durham, NC 27708, USA E-mail: ashutosh.chilkoti@duke.edu 1. Introduction Synthetic nanoparticles are beginning to make an impact on drug delivery because of their many favorable attrib- utes. They are capable of (i) encapsulating and protecting a drug cargo from premature clearance and degradation before reaching the target site; (ii) improving drug accu- mulation at the diseased site while minimizing toxicity to normal cells through passive and active targeting; and (iii) providing a tunable and controllable drug release pro- file, which can be achieved by modifying their composi- tion, architecture, and size. At the same time, they also suffer from the following limitations: (i) noncovalent self- assembled nanoparticles can be unstable in circulation; (ii) synthetic nanoparticles are opsonized by plasma proteins, which can lead to rapid clearance by the immune cells; (iii) they have limited ability to cross biological barriers; (iv) some nanoparticles, depending on their composition, are innately toxic; and (v) their biodistribution, while often superior to free drug, is often still sub-optimal in terms of their functional performance. To overcome these limitations, there is an ongoing effort to create biohybrid drug carriers that can capitalize on the prolonged circulation time, low immunogenicity, and targeting ability of native cells and biomolecules. These biohybrid delivery systems can be classified into two categories. The first category includes cell-based sys- tems, where various eukaryotic cells, such as red blood cells (RBCs), immune cells, platelets, stem cells, and cancer cells, are either used to carry drug-loaded synthetic par- ticles or are used as an inspiration to create synthetic mimetics. The second category includes biomolecule- based systems, where synthetic particles are either coated with native biomolecules or are engineered to “hitchhike” onto endogenous biomolecules—mostly proteins—in [†] These authors contributed equally to this work. Macromol. Biosci. 2017, , 1600361