‘Smartening’ anticancer therapeutic nanosystems using biomolecules Rebeca Nu ´n ˜ ez-Lozano 1 , Manuel Cano 1 , Bele ´n Pimentel 1,2 and Guillermo de la Cueva-Me ´ ndez 1 To be effective, anticancer agents must induce cell killing in a selective manner, something that is proving difficult to achieve. Drug delivery systems could help to solve problems associated with the lack of selectivity of classical chemotherapeutic agents. However, to realize this, such systems must overcome multiple physiological barriers. For instance, they must evade surveillance by the immune system, attach selectively to target cells, and gain access to their interior. Furthermore, there they must escape endosomal entrapment, and release their cargoes in a controlled manner, without affecting their functionality. Here we review recent efforts aiming at using biomolecules to confer these abilities to bare nanoparticles, to transform them into smart anticancer therapeutic nanosystems. Addresses 1 Synthetic Biology and Smart Therapeutic Systems Group, Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Parque Tecnolo ´ gico de Andalucı´a, C/ Severo Ochoa, 35, 29590 Campanillas, Ma ´ laga, Spain 2 Unit for Methodological and Statistical Support, Andalusian Public Foundation for Health and Biomedical Research in Malaga (FIMABIS), Avd. Jorge Luis Borges, 15, 29010 Ma ´ laga, Spain Corresponding author: de la Cueva-Me ´ ndez, Guillermo (gdelacueva@bionand.es) Current Opinion in Biotechnology 2015, 35:135–140 This review comes from a themed issue on Pharmaceutical biotechnology Edited by Guillermo de la Cueva-Me ´ ndez and Dror Seliktar http://dx.doi.org/10.1016/j.copbio.2015.07.005 0958-1669/# 2015 Elsevier Ltd. All rights reserved. Introduction In spite of worldwide efforts to better understand, pre- vent, detect and treat cancer, this disease killed more than 8 million people in 2012. Furthermore, the global cancer burden is expected to nearly double over the next 15 years and therefore, unless more effective therapies are devel- oped, cancer could be killing over 13 million people yearly by 2030 [1,2]. Surgery and radiotherapy remain the cornerstones of treatment for early-stage cancer, but their practicability and efficacy are limited when cancer cells have already metastasized, a pathological feature that accounts for 90% of human cancer deaths [3]. In those cases, therapeutic decisions depend on the type of cancer, metastatic burden, patient symptoms, and several predic- tive factors but, most frequently, they involve systemic administration of antineoplastic agents. Tumors require feeding blood vessels to grow, and there- fore intravenous administration is used to let chemother- apeutic drugs reach diseased cells dispersed throughout the body. However, to be effective, these agents must not only induce cell killing, but also do so in a selective manner. Unfortunately, developing drugs that meet these two requirements is proving very difficult, and virtually all cytocidal chemotherapeutic agents also harm healthy cells. This provokes undesired side effects that hinder progress towards effective treatments for the disease. A possible way to reduce off-target toxicity is to load anticancer drugs into tumor-targeting nano-carriers that can be administered systemically and release their car- goes when diseased locations are reached. This strategy reduces the distribution volume of drugs in vivo, avoiding indiscriminate exposure of healthy tissues to these agents, and therefore side effects. Different types of particles may be used as core structural elements in these drug- transporting systems but, to achieve a therapeutic effect, they have to accumulate in tumors selectively and in appropriate numbers, for which multiple physiological barriers must be overcome first (Figure 1). For instance, to achieve appropriate circulation times, these systems must avoid surface ‘fouling’ by nonspecific adsorption of serum proteins (i.e. opsonization), and the concomitant attack by cells of the reticuloendothelial system (RES) [4]. They must be able also to exit the vascular system at diseased locations, and establish strong physical contact with target cells there. Ideally, these systems should gain access into targeted cells and, once there, release their cargoes in a controlled manner, avoid- ing cellular mechanisms deployed to destroy or expel the latter. Of course such systems should be made of biode- gradable parts, to limit their long-term post-operational stability and minimize the concomitant risks of toxicity. On their own, bare nanoparticles (NPs) do not overcome such barriers efficiently, and therefore they constitute poor drug delivery systems. However, nature has provid- ed nanotechnologists with a plethora of molecules that can be used as additional building blocks to transform Available online at www.sciencedirect.com ScienceDirect www.sciencedirect.com Current Opinion in Biotechnology 2015, 35:135–140