Next-generation gene therapy for infectious disease: Advances, challenges, and future directions

Infectious diseases, worsened by antimicrobial resistance and limitations of conventional treatments, demand innovative solutions. This systematic review evaluates recent advances in next-generation gene therapy for HIV, HBV, HPV, and multidrug-resistant(MDR) pathogens, while addressing key challenges and future directions. Following PRISMA guidelines, major databases were searched (2015-2025), yielding 1250 records. the114 peer-reviewed studies were included, assessed using the MMAT, and thematically synthesized for therapeutic strategies, efficacy, challenges, and prospects. Findings show CRISPR-based genome editing achieved HIV remission in preclinical and early clinical trials, engineered bacteriophages demonstrated strong efficacy against MDR bacteria, RNAi effectively silenced HBV, and phage-derived depolymerases reduced MDR biofilms. Adverse events included off-target effects, immunogenicity, and scalability issues. Efficacy varied, with CRISPR offering high specificity and phage therapies showing robust lysis. In conclusion, Gene therapy shows strong potential against resistant pathogens, but faces challenges like study heterogeneity, preclinical reliance, delivery barriers, and unequal access in low-and middle-income countries.