Among a variety of drug administration routes, the oral route is the most preferred due to better safety profiles, convenience of administration, high patient compliance, and low manufacturing costs [1,2]. Thus, oral formulations are always the first choice in early-stage formulation development [3]. Nonetheless, oral drug delivery is confronted with numerous challenges because of the harsh gastrointestinal factors that may hinder oral drug absorption, including but not limited to strong gastric acidity, a wide pH gradient from pH 1.2 in the stomach to pH 7.0 in the colon, multiple digestive enzymes, a thick layer of mucus overlaying the epithelia, and enteric epithelial barriers composed of different types of cells connected by tight junctions (TJs) [4]. Only drugs with high solubility, high permeability, and high stability can achieve reasonable oral bioavailability. A large number of orally administered drugs, especially biomacromolecules, encounter difficulties in absorption [5].

After oral absorption, the drug entities may take either the bloodstream or lymphatics to reach the systemic circulation and then be transported to different sites of the body to elicit therapeutic effects. The destiny of a drug molecule depends on its predisposition for different targets. If the molecules are designed to bind specific receptors at the target site, molecular targeting could thus be realized. Therefore, one of the challenges of modern drug development is to discover and design molecules that possess both trans-intestinal and targeting capabilities, such as the recently booming small-molecule PD-1/PD-L1 antagonists that can be administered orally [6]. Nevertheless, the in vivo fate of drug entities is subject to a variety of challenges before they ultimately reach their destination.

Drug entities should first survive the gastrointestinal environment, then penetrate the enteric epithelia, circumvent blood clearance, and finally be transported to their destination. In recent years, a number of approaches have been established to realize efficient oral drug delivery by 1) modifying the structure of drug molecules, 2) proactively manipulating the gastrointestinal environment, and 3) exploiting the delivery capacity of micro- or nanocarriers [7]. Through the introduction or replacement of functional groups, the physicochemical properties of therapeutics can be rendered amenable for oral administration. For example, to acquire an appropriate logP value, which is a prerequisite for oral absorption, it is common to introduce hydrophilic groups such as phosphate esters to poorly soluble drugs or to mask polar groups such as carboxyl groups of poorly permeable drugs [8]. Moreover, it is also common to conjugate peptides with polymers to ameliorate their liability by virtue of the steric hindrance effect against proteolytic degradation [9]. However, in addition to altering the drug molecules themselves, researchers sometimes resort to active interventions in the gastrointestinal environment. In this case, specific excipients such as pH modifiers, enzyme inhibitors, and permeation enhancers are employed to address the issues of polytropic pH, hydrolases, and mucus layers [4,10,11]. Although the former two strategies have played significant roles in overcoming gastrointestinal barriers for years, growing attention has recently been paid to carrier drug delivery systems (CDDSs). Carrier matrices create physical barriers that prevent drug payloads from being degraded directly by unfriendly factors in the body while realizing sustained or controlled release. More importantly, the physicochemical and surface properties of carrier systems can be tailored to enable programmed drug delivery [12,13]. For instance, the large surface area of carrier systems provides a platform for surface modifications for targeted drug delivery. Carriers can be either microcarriers or nanocarriers, named after their micrometer or nanometer sizes. As nanocarriers are more commonly investigated, this term is used to refer to carriers in the context of this article, unless specified otherwise.

Compared to conventional formulations, targeted nanocarriers have the ability to deliver drugs selectively to diseased sites with increased efficacy and decreased side effects [14]. The most common route to achieve targeted drug delivery by carrier systems is through the parenteral route. Most of the nanomedicines marketed thus far are administered intravenously [15]. However, it is neither an economic nor a convenient route for drug administration owing to the requirements of professional practitioners and the potential risks of cross infections. In contrast, oral administration allows for self-administration at home in addition to the advantages mentioned above, which not only eases the strain of medical resources but also enhances patient adherence, especially for patients with chronic diseases who need long-term medication [16].

Traditionally, oral CDDSs aim at targeted drug delivery to local sites along the gastrointestinal tract (GIT), in addition to sustained or controlled drug release purposes, to treat locoregional diseases such as Helicobacter pylori infection and inflammatory bowel diseases [17,18]. However, this is not the topic of this review. Readers are referred to recent reviews for a glimpse of the state of the art of oral targeted delivery within the GIT, which is also termed oral site-specific delivery [19,20]. The current review will focus on a more controversial topic-oral targeted delivery to sites beyond the GIT (Fig. 1). Recent findings demonstrate that some nanocarriers can translocate across the GIT and reach remote sites [21,22]. This raises interesting speculation on oral targeted delivery to treat diseases at distant sites, such as tumors and infections. The key point lies in how many carriers can be transported across the GIT and finally reach the target sites as the natural defense mechanisms in the GIT and apparently wandering long march prevents them from reaching the circulation. Nevertheless, recent evidence emerges to support the oral absorption of integral particles via specific pathways such as the microfold (M) cell-to-lymphatics pathway [[21], [22], [23]].

As the absorption of intact nanocarriers is a prerequisite for oral targeted delivery, existing evidence that supports this assumption is first introduced, followed by a description of possible transepithelial absorption pathways. Furthermore, as an important factor, the formation of biological coronas, especially protein coronas, during the trans-gastrointestinal process is elaborated. Finally, oral targeted delivery to post-GIT sites for the potential treatment of diseases, including tumors, inflammation, and infections, is summarized. To date, there are no up-to-date reviews published on this emerging topic. This review tends to clarify some of the fundamental concepts, provide an overview of the status quo, and evoke beneficial discussion to accelerate research in this field.