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Page 4 of 25 Luo et al. Microbiome Res Rep 2025;4:10 https://dx.doi.org/10.20517/mrr.2024.57

Figure 1. Mechanistic insights into the application of engineered bacterial-based in vivo drug delivery systems for disease therapy. (A)
Intestinal in situ production of anti-inflammatory mediators; (B) Diabetes therapy in animal models; (C) Antitumor strategy; (D)
Neurodegenerative disease intervention.

intestinal mucosal barrier in UC, caused by an imbalanced intestinal microecology, leads to inappropriate
immune system activation and subsequent tissue damage . Additionally, reactive oxygen species (ROS)
[29]
and protein hydrolases released by neutrophils during intestinal inflammation can disrupt tight junctions
between intestinal epithelial cells, further compromising the intestinal barrier . Furthermore, short-chain
[30]
fatty acids, which are metabolites of intestinal microorganisms, have been shown to regulate the quantity
and function of Tregs, thereby modulating the immune status of the gut .
[31]

Improving the inflammatory state of the intestine is a key focus in the treatment of IBD. Traditional
therapies typically involve the use of anti-inflammatory drugs and immunosuppressive agents, such as anti-
TNF-α antibodies. Excessive exposure of active drugs to the intestinal lumen can lead to their absorption
into the systemic circulation through the intestinal mucosa, potentially triggering adverse reactions . To
[32]
minimize unnecessary drug exposure and related side effects, an in vivo drug delivery system based on
engineered bacteria has been developed, which enables targeted colonization . In 2000, Steidler et al. first
[33]
reported the use of engineered Lactococcus lactis to deliver mIL-10 for the treatment of IBD in mice . In
[34]
this study, the mIL-10 gene sequence was cloned into a plasmid and introduced into Lactococcus lactis via
electrotransformation, enabling the bacteria to produce mIL-10. However, the potential accumulation of
transgenic strains raised biosafety concerns. To address this, Steidler et al. utilized a clever biocontainment
strategy: they constructed a homology arm containing the upstream and downstream regions of the thyA
gene, which, when introduced into Lactococcus lactis along with an hIL-10 expression cassette, allowed for
the replacement of thyA with hIL-10 through double homologous recombination . Subsequent clinical
[35]
trials confirmed the efficacy of both the biocontainment strategy and the therapeutic approach .
[36]