Bioinspired drug delivery strategies for repurposing conventional antibiotics against intracellular infections.

Bacteria have developed a wealth of strategies to avoid and resist the action of antibiotics, one of which involves pathogens invading and forming reservoirs within host cells. Due to the poor cell membrane permeability, stability and retention of conventional antibiotics, this renders current treatments largely ineffective, since achieving a therapeutically relevant antibiotic concentration at the site of intracellular infection is not possible. To overcome such challenges, current antibiotics are 'repurposed' via reformulation using micro- or nano-carrier systems that effectively encapsulate and deliver therapeutics across cellular membranes of infected cells. Bioinspired materials that imitate the uptake of biological particulates and release antibiotics in response to natural stimuli are recently explored to improve the targeting and specificity of this 'nanoantibiotic' approach. In this review, the mechanisms of internalization and survival of intracellular bacteria are elucidated, effectively accentuating the current treatment challenges for intracellular infections and the implications for repurposing conventional antibiotics. Key case studies of nanoantibiotics that have drawn inspiration from natural biological particles and cellular uptake pathways to effectively eradicate intracellular pathogens are detailed, clearly highlighting the rational for harnessing bioinspired drug delivery strategies.