Helicobacter pylori infection is strongly associated with chronic gastritis, peptic ulcers, and gastric cancer. Antibiotic resistance in H. pylori is an increasingly serious threat to global public health. Although oral vaccination is considered to be a promising strategy for protection against H. pylori infection, the poor efficacy of oral vaccines remains a major challenge due to their poor ability to penetrate mucus and cross transepithelial absorption barriers. This study reports the development of a well‐designed nanoparticle that is electrostatically self‐assembled with antigen and cell‐penetrating peptide (CPP), and then coated with a “mucus‐inert” PEG derivative. The nanoparticles have hydrophilic and slightly negative surface properties, which confers excellent mucus‐penetrating ability. Studies demonstrate that the self‐assembled PEG derivatives gradually dissociate from the nanoparticles in mucus, exposing the CPP‐rich cores that are efficiently transepithelial transported via intracellular and paracellular pathways. Nanoparticles containing recombination urease subunit B, a candidate vaccine against H. pylori, significantly enhance systemic and mucosal antibody levels in mice, and these immune responses protect the animals from H. pylori challenge. These results suggest that the CPP‐rich PEGylated nanoparticles may be a powerful platform for building an oral vaccine to protect against gastrointestinal infection by recalcitrant H. pylori or/and other pathogenic microorganisms.

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Inducing immune tolerance through repeated administration of self-antigens is a promising strategy for treating rheumatoid arthritis (RA), and current research indicates that coadministration of immunomodulators can further orchestrate the tolerogenic response. However, most of the clinical trials based on tolerance induction have negligible therapeutic effects. Peripheral lymphoid organs play critical roles in immunotherapy. Here, we design an engineered nanoemulsion for targeted codelivery of self-antigens and an immunomodulator to ectopic lymphoid structures (ELSs) in inflamed joints of RA. Namely, a citrullinated multiepitope self-antigen (CitP) and rapamycin are incorporated into the nanoemulsions (NEs@CitP/Rapa), which are fabricated by a facial method using commercialized pharmaceutical excipients. After intravenous administration, the nanoemulsion shows satisfactory accumulation in the inflamed paws and provides enhanced anti-inflammatory effect in various experimental murine models of RA. Our study provides a promising targeting strategy to induce immune tolerance for the treatment of RA.