Dopamine Polymerization-Mediated Surface Functionalization toward Advanced Bacterial Therapeutics

Bacteria-based therapy has spotlighted an unprecedented potential in treating a range of diseases, given that bacteria can be used as both drug vehicles and therapeutic agents. However, the use of bacteria for disease treatment often suffers from unsatisfactory outcomes, due largely to their suboptimal bioavailability, dose-dependent toxicity, and low targeting colonization. In the past few years, substantial efforts have been devoted to tackling these difficulties, among which methods capable of integrating bacteria with multiple functions have been extensively pursued. Different from conventional genetic engineering and modern synthetic bioengineering, surface modification of bacteria has emerged as a simple yet flexible strategy to introduce different functional motifs. Polydopamine, which can be easily formed via in situ dopamine oxidation and self-polymerization, is an appealing biomimetic polymer that has been widely applied for interfacial modification and functionalization. By virtue of its catechol groups, polydopamine can be efficiently codeposited with a multitude of functional elements on diverse surfaces. In this Account, we summarize the recent advances from our group with a focus on the interfacial polymerization-mediated functionalization of bacteria for advanced microbial therapy. First, we present the optimized strategy for bacterial surface modification under cytocompatible conditions by in situ dopamine polymerization. Taking advantage of the hydrogen bonding, pi-pi stacking, Michael addition, and Schiff base reaction with polydopamine, diverse functional small molecules and macromolecules are facilely codeposited onto the bacterial surface. Namely, monomodal, dual-modal, and multimodal surface modification of bacteria can be achieved by dopamine self-deposition, codeposition with a unitary composition, and codeposition with a set of multiple components, respectively. Second, we outline the regulation of bacterial functions by surface modification. The formed polydopamine surface endows bacteria with the ability to resist in vivo insults, such as gastrointestinal tract stressors and immune clearance, resulting in greatly improved bioavailability. Integration with specific ligands or therapeutic components enables the modified bacteria to increase targeting accumulation and colonization at lesion sites or play synergistic effects in disease treatment. Bacteria codeposited with different bioactive moieties, such as protein antigens, antibodies, and immunoadjuvants, are even able to actively interact with the host, particularly to elicit immune responses by either suppressing immune overactivation to promote the reversion of pathological inflammations or provoking protective innate and/or adaptive immunity to inhibit pathogenic invaders. Third, we highlight the applications of surface-modified bacteria as multifunctional living therapeutics in disease treatment, especially alleviating inflammatory bowel diseases via oral delivery and intervening in different types of cancer through systemic or intratumoral injection. Finally, we discuss the challenges and prospects of dopamine polymerization-mediated multifunctionalization for preparing advanced bacterial therapeutics as well as their bench to bedside translation. We anticipate that this Account can provide an insightful overview of bacterial therapy and inspire innovative thinking and new efforts to develop next-generation living therapeutics for treating various diseases.