Bingxian Li, Huihui Mu, Xiting Lin, Daniel Cung Tha Thawng, Gang Li, Yanhui Yang
With the escalating crisis of antimicrobial resistance, the slow pace of traditional antibiotic development presents a critical and growing threat to global public health. Phage therapy, which offers benefits such as high specificity, self-replication, and minimal disruption to the microbiota, has emerged as a promising treatment option. However, its therapeutic potential faces several hurdles, including a limited antibacterial spectrum, inadequate in vivo efficacy, susceptibility to immune clearance, and inability to target intracellular bacteria and biofilm-associated infections. To overcome these issues, new delivery systems have been developed by combining engineered phages with functional materials, such as nanomaterials, hydrogels, and liposomes. This approach significantly improves phage targeting, stability, drug delivery capacity, and controlled release. Nevertheless, engineered phages face challenges such as complex host interactions and intestinal delivery. Future research should incorporate artificial intelligence-assisted design, cross-disciplinary teamwork, and innovative materials to develop phage delivery systems as groundbreaking tools against drug-resistant infections and complex diseases. This review discusses the potential uses of engineered phages in combination with antibiotic therapy, clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein gene editing, innovative smart drug delivery, and tumor immune environment control. It also examines the key challenges in translating laboratory studies to clinical use, including technical issues, immune response regulation, and safety concerns.