pharmaceutics Review Recent Advances in Nanocarrier-Assisted Therapeutics Delivery Systems Shi Su and Peter M. Kang * Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, 3 Blackfan Circle, CLS 910, Boston, MA 02215, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-617-735-4290; Fax: +1-617-735-4207 Received: 30 June 2020; Accepted: 28 August 2020; Published: 1 September 2020 Abstract: Nanotechnologies have attracted increasing attention in their application in medicine, especially in the development of new drug delivery systems. With the help of nano-sized carriers, drugs can reach specific diseased areas, prolonging therapeutic efficacy while decreasing undesired side-effects. In addition, recent nanotechnological advances, such as surface stabilization and stimuli-responsive functionalization have also significantly improved the targeting capacity and therapeutic efficacy of the nanocarrier assisted drug delivery system. In this review, we evaluate recent advances in the development of different nanocarriers and their applications in therapeutics delivery. Keywords: nanomedicine; nanocarriers; drug delivery 1. Introduction Nanotechnology has emerged to be an area of active investigation, especially in its applications in medicine [1]. The nanoscale manipulation allows optimal targeting and delivery as well as the controllable release of drugs or imaging agents [2]. Among all the applications of nanotechnology in medicine, nanocarrier assisted drug delivery system has attracted significant research interest due to its great translational value. The small size of the nanocarriers can help drugs overcome certain biological barriers to reach diseased areas [3,4]. Taking advantage of different nano-sized materials and various structures, nanocarriers can help poorly soluble drugs become more bioavailable and protect easily degraded therapeutics from degradation [5,6]. In addition, the modifiable surfaces of nanocarriers also expand their usability in different biomedical applications, especially in targeted therapy [7]. Indeed, their modification can not only stabilize but also functionalize them to be responsive to different stimuli, improving the therapeutic efficacy [7]. Herein we review recent advances in the development and applications of various nanocarriers, discussing their advantages and disadvantages in terms of their different compositions as well as different functionalization techniques. As the nanocarrier assisted drug delivery system is a broad field under active investigation, in order to provide a more in-depth review, after an overview of different types of nanocarriers, we will focus on stimuli-response nanocarriers. 2. Methods This review was written in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) protocol [8]. We used PubMed as our database, and searched original research articles and relevant reviews by entering keywords such as “nanomedicine” and “drug delivery.” Search results were critically analyzed and categorized by the nature of the drug delivery system. Pharmaceutics 2020, 12, 837; doi:10.3390/pharmaceutics12090837 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2020, 12, 837 2 of 25 Pharmaceutics 2020, 12, x 2 of 27 3. Types of Nanocarriers 3. Types of Nanocarriers Nanocarrier assisted drug delivery systems have gained increasing recognition in recent years for Nanocarrier assisted drug delivery systems have gained increasing recognition in recent years biomedical applications. As different clinical needs require different types of drug delivery systems, for biomedical applications. As different clinical needs require different types of drug delivery various designs of nanocarriers are being developed in order to meet specific requirements. There are systems, various designs of nanocarriers are being developed in order to meet specific requirements. a variety of nanocarriers for the drug delivery categorized by different compositions and structures, There are a variety of nanocarriers for the drug delivery categorized by different compositions and including carbon nanotubes, carbon dots, polymeric micelles, liposomes, iron oxide nanoparticles, structures, including carbon nanotubes, carbon dots, polymeric micelles, liposomes, iron oxide nanogels, and dendrimers [7,9] (Figure1). nanoparticles, nanogels, and dendrimers [7,9] (Figure 1). Figure 1. Schematic illustration of some nanocarriers. Figure 1. Schematic illustration of some nanocarriers. 3.1. Liposomes 3.1. Liposomes Liposomes are phospholipid vesicles consisting of lipid bilayers enclosing discrete aqueous spacesLiposomes [10,11]. Several are phospholipid features of liposomesvesicles consisting make them of goodlipid candidatesbilayers enclosing as drug deliverydiscrete systems.aqueous Thesespaces self-assembled [10,11]. Several nanocarriers features of areliposomes biocompatible, make them easily good modifiable, candidates and as capable drug delivery of carrying systems. large drugThese payloads self-assembled [10]. Liposomes nanocarriers are are able biocompatible, to entrap both easily lipophilic modifiab andle, hydrophilic and capable compounds of carrying (drugs large anddrug/or payloads imaging [10]. agents), Liposomes in the are lipid able membrane to entrap andboth thelipophilic aqueous and core, hydr respectivelyophilic compounds [12]. They (drugs are alsoand/or generally imaging considered agents), in tothe have lipid a membrane good safety and profile the aqueous [10]. Conventional core, respectively liposomal [12]. They nanocarriers are also aregenerally simple considered self-assembled to have lipid a good bilayers safety carrying profile therapeutics [10]. Conventional in their liposomal aqueous cores.nanocarriers The lipid are bilayerssimple self-assembled can be further lipi stabilizedd bilayers by addingcarrying polyethylene therapeutics glycol in their (PEG) aqueous to the cores. surface, The a lipid modification bilayers calledcan be PEGylationfurther stabil [13ized]. Liposomes by adding can polyethylene also be functionalized glycol (PEG by) to modifying the surface, the a surface modification with specific called ligandsPEGylation [10]. [13]. Furthermore, Liposomes they can also can be functionaliz equipped withed by imaging modifying agents the onsurface the surface with specific together ligands with the[10]. targeting Furthermore, ligand they to improve can be targeting equipped effi withciency im whileaging possessing agents on boththe therapeuticsurface together and diagnostic with the (theranostic)targeting ligand properties to improve [10]. Thetargeting major biologicalefficiency challengewhile possessing of liposomal both carriers therapeutic is their and fast diagnostic clearance by(theranostic) the reticuloendothelial properties [10]. system The (RES)major [10biological]. Even thoughchallenge surface of liposomal modification carriers of liposomes is their fast by PEGylationclearance by can the significantly reticuloendothel minimizeial system their uptake (RES) by [10]. the RES,Even the th clearanceough surface cannot modification be completely of avoidedliposomes [10 by]. ConstantPEGylation modifications can significantly have alsominimize been made their uptake in order by to the improve RES, the the clearance targeting cannot efficiency be andcompletely therapeutic avoided efficacy [10]. of Constant liposomes modifications while decreasing have their also toxicitybeen made [10]. Inin orderorder totoovercome improve thethe challengetargeting efficiency of being quickly and therapeutic cleared by efficacy the RES, of lipo Tangsomes et al. while reported decreasing a new modification their toxicity to [10]. the In surface order ofto theovercome liposome the with challenge a “do not-eat-me” of being quickly strategy clea [14].red Inspired by the by RES, the findingsTang et that al. thereported expression a new of CD47modification is upregulated to the surface on the of surface the liposome of certain with cancer a “do cells not-eat-me” to avoid phagocytosis, strategy [14]. this Inspired strategy by wasthe achievedfindings that by adding the expression a CD47-derived, of CD47 enzyme-resistant is upregulated on peptide the surface to the surfaceof certain of thecancer liposome cells to in avoid order tophagocytosis, block the RES this so strategy that the was circulation achieved time by ofadding the liposome a CD47-derived, can be prolonged enzyme-resistant [14,15]. peptide to the surfaceLiposomal of the liposome carriers havein order been to widely block the used RES as nanocarriersso that the circulation for drugdelivery time of the asthey liposome have showncan be significantprolonged improvement[14,15]. in therapeutic efficacy by stabilizing the payload and assisting targeted tissue uptakeLiposomal [10,11,16 ].carriers The Food have and been Drug widely Administrations’ used as nanocarriers (FDA) first for approval drug delivery of Doxil, as they a liposomal have shown drug carryingsignificant an improvement anti-cancer agent- in therapeutic doxorubicin efficacy hydrochloride, by stabilizing has paved the the payload way for and the clinicalassisting translation targeted oftissue nanocarriers uptake [10,11,16]. [9]. In subsequent The Food years, and liposomes Drug Admi continuenistrations’ to be the (FDA) dominant first nanocarrierapproval of among Doxil, all a theliposomal nanocarrier-assisted drug carrying drugan anti-cancer submissions agent- to the doxorubicin FDA, suggesting hydrochloride, the safety has and paved