Drug delivery by erythrocytes: "Primum non nocere"

Red blood cells (RBCs) are naturally capable of transporting diverse cargoes throughout the circulatory system, both loaded to their surface or within their inner volume. Starting largely from the 1970s, diverse approaches for encapsulation into, and surface coupling onto, RBCs have been investigated as potential drug delivery systems. In the last decade, these efforts have yielded diverse strategies to load drugs and nanocarriers to RBCs, and to optimize their pharmacokinetics, distribution, and effects in the body. Several formulations of donor RBCs encapsulated with enzymes and drugs are currently undergoing clinical trials for treatment of oncologic and neurologic conditions. Newer approaches include design of drugs with an affinity to circulating RBCs, encapsulation into RBCs using membrane permeating compounds, and design of hybrid drug delivery systems combining synthetic components with fragments of RBC membranes. Notwithstanding the growing enthusiasm and optimism in RBC drug delivery, in this article we discuss potentially problematic issues of this biomedical concept, especially impairment of biocompatibility of the carrier RBCs, and other adverse and unintended effects. Rigorous and systematic analysis of the cautionary aspects described in this article should be further developed and extended in order to soberly gauge the risk/benefit balance of any given RBC-based drug delivery application. While there is little doubt that RBC drug delivery will ultimately flourish, focusing research efforts on approaches that are unlikely to cause adverse effects in patients will help to sooner bring this day.