Rational Design of Oral Vaccines by Gut Organoid Mucosal Models

In the age of the COVID-19 pandemic, the significance of effective oral vaccines is as high as it has ever been. Effective oral vaccine requires high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads (i.e., immunogens) against gastric damage. In this study, hollowed nanocarriers (NCs: silica nanospheres and gold nanocages) with poly-l-lysine (PLL) coating and mammalian orthoreovirus cell attachment protein σ1 functionalization (NC-PLL-σ1) were explored as oral vaccine delivery vehicles (OVDVs). The transport of these OVDVs to mucosal lymphoid tissues could be facilitated by microfold (M-cells) mediated transcytosis (via σ1-α2–3-linked sialic acids adherence) across gastrointestinal epithelia. PLL coating provided protection and slow-release of rhodamine 6 G (R6G), a model payload. The transport effectiveness of these OVDVs was tested on intestinal organoid monolayers in vitro. When compared with other experimental groups, the complete OVDV system (with PLL-σ1) demonstrated two significant advantages: a significantly higher transport efficiency (198% over blank control at 48 hrs); and protection of payloads which led to both better transport efficiency and extended-release of payloads (61% over uncoated carriers at 48 hrs) which could enhance vaccine efficacy. In addition, it was shown that the M cell presence in intestinal organoid monolayers (modulated by Rank L stimulation) was a determining factor on the transport efficiency of the OVDVs: more M-cells (induced by higher Rank L) in the organoid monolayers led to higher transport efficiency for OVDV-delivered model payload (R6G). The complete OVDVs showed a great potential as effective oral vaccine and/or drug delivery vehicle.