SORTing the Fate of Nanodelivery Systems

Abstract

With the rapid development of nanotechnology, the role of nanocarriers in biomedicine is becoming increasingly important. The bottleneck, however, is efficient delivery of nanomedicine to specific organs or specific lesions, and it has been a hotspot in nanomedicine circles [1]. In general, the targeting of nanocarriers can be divided into two major directions. One is passive targeting, that is, the ability of nanocarriers to target specific sites depends on nano-inherent characteristics and the physiological characteristics of the lesion site. For example, nanocarriers (∼10 to 100 nm) are considered optimal for in vivo targeting delivery due to the enhanced permeability and retention (EPR) effect, which occurs only in the vicinity of tumors [2]. Increased angiogenesis leads to rapid development of blood vessels for tumor growth, which leads to significant increase in vascular permeability in the tumor area compared with healthy tissues [3, 4]. In addition, for specific microenvironmental changes in tumor or lesion sites, including weak acidity, enzyme overexpression, high levels of redox, etc., the design of targeted responsive-nanomaterials under the above special conditions has also been a focus of research in recent years [5–7]. The second direction is active targeting, that is, modifying special ligands or antibodies on the surface of nanocarriers to actively target organs and tissues expressing the corresponding receptors. For example, due to the high expression of alpha V beta III (α V β 3 ) integrin in tumor blood vessels, the attachment of the RGD peptide, which can specifically target α V β 3 on the surface of nanocarriers, can significantly increase the tumor targeting ability of nanodrugs [8, 9]. On the whole, to improve the targeting of liposomes, nano-micelles, or other nanocarriers, their stability and targeting should be improved through physical or biochemical methods. PEGylated nanocarriers greatly prolong the stability of nanocarriers and solve the nanocarriers’ inability to circulate in the blood for a long time [9, 10]. However, how to prevent nanocarriers from targeting other organs or tissues besides the liver is an unsolved problem. According to our current understanding, nanomedicines exhibit distinct liver affinity after systematic injection because of their natural physiological advantages, including slow blood flow [11, 12] and discontinuous vasculature in hepatic sinusoids [13]. This targeting mechanism is similar to the tumor EPR effect mentioned above, which takes advantage of the discontinuity of vascular endothelium and the retention of nano-sized substances. It is exciting to see new advances in the targeting of other organs and tissues besides the liver. James E. Dahlman previously reported a system called Fast Identification of Nanoparticle Delivery (FIND), which is capable of simultaneously quantifying >100 lipid nanoparticles (LNPs) delivering mRNA to multiple cell types in vivo [14]. They quantified more than 250 LNPs in vivo and identified two formulations that deliver RNA to endotheliocytes. The screening system uses designed DNA barcodes and the Cre-Lox animal model. After intravenous administration, flow cytometry and high-throughput sequencing systems are required to determine the cell distribution of different LNPs. Although this is a good screening platform, it is expensive and time consuming, and ordinary researchers may not have the capability to set up such a laboratory. Therefore, a predictable and efficient system to enhance the targeting ability and performance of nanocarriers to target organs is urgently needed. In another study, Cheng et al. [15] proposed an intelligent approach called Selective Organ Targeting (SORT), which targets different organs, including the liver, spleen, and lung, based on charge regulation and transformation within the nanoparticles itself. Traditional LNPs are composed of cationic lipids, amphipathic phospholipids, 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yatsen University, Guangzhou 510120, China