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administration [133,145] . Antigen presentation on the bacterial surface, facilitated by an AIDA autotransporter
or an anchoring matrix, is crucial as it enhances stimulation of the local mucosa-associated lymphoid tissue
(lamina propria). In comparable oral administration settings, engineered Lactobacillus casei utilized PgsA as
an anchoring matrix to fuse K99 and K88 fimbrial proteins, achieving higher levels of specific IgA and IgG
antibodies and eliciting effective T cell immune responses. This outperformance contrasts with engineered
EcN, where the plasmid was directly inserted into the K88 fimbrial adhesin gene [146,147] . In both studies,
Lactobacillus casei demonstrated higher immunogenicity compared to EcN, highlighting that the choice of
chassis bacteria can significantly impact the efficacy of mucosal vaccines.

Advantages and deficiencies of engineered bacteria in disease treatment
Engineered bacteria play a pivotal role as carriers in drug delivery systems, providing a promising platform
to enhance the precise delivery of drugs or target molecules to lesions for targeted therapy. This
development is particularly significant in treating hypoxic solid tumors such as melanoma, where
conventional radiotherapy and chemotherapy often struggle due to their low tumor-targeting efficiency and
limited tissue penetration. Engineered attenuated Salmonella typhimurium, capitalizing on its facultative
anaerobic nature, exhibits a remarkable ability to target and colonize hypoxic tumor tissues. Moreover,
releasing mPD-1 modulates immunity, leading to a substantial reduction in tumor volume . Additionally,
[97]
strategies such as surface modification, ecological niche competition, and genetic engineering further
augment the efficacy of these targeting approaches .
[148]

In the treatment of IBD, conventional high-dose administration of anti-inflammatory factors such as IL-10,
IL-27, or IL-35 is expensive and often results in significant systemic side effects . However, engineered
[149]
Lactococcus lactis can locally produce IL-10 in the intestine upon topical application, effectively reducing
systemic side effects associated with high-dose treatments . Moreover, probiotics themselves can modulate
[35]
intestinal microecology and promote mucosal repair, thereby enhancing the effectiveness of engineered
[150]
bacteria . Engineered bacteria also address challenges related to the short half-life of certain drug
molecules. For example, in the treatment of neurodegenerative diseases and diabetes mellitus, engineered
EcN and Lactobacillus lactis can consistently and efficiently express GLP-1, which reduces drug dosage,
minimizes side effects, and improves patient adherence [111,151] . Furthermore, patients with PKU often face a
reduced quality of life due to strict Phe restrictions. Traditional treatments involve daily subcutaneous
injections of recombinant PAL, which are effective in some patients but can induce severe allergic
reactions . Engineered bacterium SYNB1618, expressing PAL, presents a promising solution with
[152]
[76]
demonstrated safety and tolerability in clinical trials .
While natural and engineered bacteria hold promise for future disease treatments, studies have highlighted
safety concerns associated with these live drugs. Engineered bacterial therapies must address both biosafety
and ethical concerns to ensure that live therapeutic bacteria do not spread or undergo unintended
recombination in the environment. Antibiotic resistance genes can be carried on mobile genetic elements
such as plasmids and transposons, facilitating their exchange through conjugative transfer between bacteria.
This horizontal transfer of resistance genes poses a significant risk. For instance, vancomycin resistance
genes have been observed to transfer from Enterococci to Lactobacillus acidophilus even without antibiotic
selection pressure, potentially occurring within the human gastrointestinal tract . In a study assessing
[153]
eight commercially available probiotic preparations containing Lactobacillus acidophilus, various resistance
genes - including those for vancomycin, ciprofloxacin, broad-spectrum β-lactamases, and tetracycline - were
detected . Without stringent screening, these probiotics could inadvertently serve as vectors for antibiotic
[154]
resistance genes.