Background

As a self component, cells exhibit inherent physiological properties in drug delivery, such as biocompatibility and homing effect (Yang et al., 2022). These help the drug payload to escape clearance by the mononuclear phagocyte system and perform the physiological function–based hitchhiking delivery. Recently, cell-based carriers were mainly constructed via direct drug internalization; this procedure was very simple, needing only in vitro cell culture with the payload (Li et al., 2021). In addition, another construction strategy was surface conjugation between cell and payload, which could be divided into covalent conjugation, receptor–ligand interaction, host–guest interaction, and physical interaction (Krueger et al., 2018; Li et al., 2018). The host cell must be artificially modified in vitro and then conjugated with payload. Thus, cell-based carriers, via either intracellular drug internalization or cell-surface attachment, were constructed in vitro before in vivo administration. This presented three challenges in clinical translation and application: 1) large-scale preparation is barely possible due to the limitation of separating sufficient number of endogenous cells; 2) in vitro drug loading processes may inevitably affect the physiological function of the carrier cells; and 3) transporting cells correspond to one single host, and would generate immune rejection when applied to other individuals.

In light of these issues, bacteria-mimetic gold nanoparticles (GNPs) were developed for in vivo construction of immune cell–based carriers and efficiently and stably hitchhiking delivery. In this design, both β-cyclodextrin (β-CD)-modified GNPs (CD-GNPs) and adamantane (ADA)-modified GNPs (ADA-GNPs) are coated by E. coli outer membrane vesicles (OMVs). Host–guest interactions involve two molecules or materials that can form complexes through unique structural relationships and noncovalent binding. Due to host–guest interactions between β-CD and ADA (Loescher and Walther, 2020; Wang et al., 2021), the host β-CD could bind with guest ADA to form a supramolecular complex. Thus, CD-GNPs bound with ADA-GNPs to produce GNP aggregates. It has been observed that the GNP aggregates show higher absorption ratio and therefore, higher temperature rise compared to single GNPs. The effect of photothermal therapy (PTT) was significantly improved in the form of GNP aggregates in comparison to GNPs. The E. coli OMVs coating induce the phagocytosis of GNPs by circulating immune cells, leading to intracellular degradation of OMVs and subsequent supramolecular self-assembly of GNPs. In addition to the increased PTT efficiency, GNP aggregation increased the nano-size of GNP into micro-size of GNP aggregate, which significantly inhibits the leakage of GNPs from immune cells (Zhang et al., 2021). This bacterial OMV-coating strategy for immune cell phagocytosis was not only applied to GNPs, but also extended to other therapeutic reagents that directly modulate immune cells or target disease tissues via immune cell hitchhiking delivery.

As different cells (platelets, stem cells, macrophages, T cells, or even tumor cells) have different physiological functions, the coating material could be specifically designed for phagocytosis according to the required type of cells as carriers for hitchhiking delivery.