Host Defense Peptides for Intracellular Bacterial Infections: Overcoming Translational Barriers Through Peptide Engineering and Nanotechnology-Based Drug Delivery Systems

Intracellular bacterial infections represent a major therapeutic challenge due to the ability of pathogens to persist within host cells, evade host immune surveillance and exhibit reduced susceptibility to conventional antibiotics. Consequently, these infections are often associated with severe clinical manifestations, antibiotic resistance, treatment failure, and increased mortality. Host-directed therapies have emerged as a promising approach by strengthening host defense mechanisms through the modulation of innate and adaptive immune responses, thereby enhancing the clearance of intracellular pathogens. Among these strategies, host defense peptides (HDPs) have gained considerable attention as they combine broad-spectrum antimicrobial activity with the ability to modulate host immune responses. HDPs also regulate the hyperinflammatory phase of infection, thereby limiting excessive tissue damage and infection-associated complications. Despite the promising preclinical efficacy against bacterial infections, the clinical translation of peptide-based therapeutics is hindered mainly by its inherent pharmacokinetic limitations, including poor stability, rapid proteolytic degradation, and limited bioavailability. However, recent advances in rational peptide engineering and nanotechnology-based delivery systems have shown considerable promise in overcoming these limitations. This review discusses the mechanisms employed by intracellular bacterial pathogens to colonize and survive within host cells. We highlight the immunomodulatory role of HDPs in controlling intracellular bacterial infections and critically examine the major barriers limiting their clinical translation. Finally, we summarize recent advances in peptide engineering and targeted delivery strategies that facilitate the development of HDP-based therapeutics for the effective treatment of intracellular bacterial infections.