Commensal-driven serotonin production modulates in vivo delivery of synthetic and viral vectors.

In vivo delivery systems (IDSs) are designed to protect and transport therapeutics, but their clinical applications are hindered by low delivery efficiency. We identified gut microbiota as key regulators of efficacy of IDS-based therapies and that disrupting commensal-host interactions markedly improves drug and gene delivery. Intestinal epithelial cells sense microbial stimulation and remotely activate Kupffer cells through serotonin production, thereby driving hepatic IDS clearance. Transient suppression of serotonin signaling, through receptor blockade or dietary intervention, mitigates hepatic IDS clearance and improves delivery efficiency. This strategy yielded more than threefold therapeutic enhancement in chemotherapy and oncolytic virotherapy and 5- to 15-fold improvements in somatic genome editing and messenger RNA–based therapies. These findings reveal a gut-liver immune axis that can be therapeutically exploited to improve IDS-based cancer and gene therapies. Editor's summary: To be effective, drugs and vaccines need to avoid degradation, reach their intended targets in the body, and minimize off-target toxicity. A variety of delivery systems, such as liposomes and nanoparticles, have been developed for this purpose in recent years, but they still have limited effectiveness, particularly because they are prone to rapid clearance by the immune system. Modifying the delivery systems themselves has not been sufficient to overcome this problem, so Wang et al. targeted the mechanisms of immune-based degradation instead. The authors discovered that the gut microbiota plays a major role in stimulating the immune clearance of various delivery vectors in the liver, identified the mechanism for this activity, and demonstrated dietary and pharmacological interventions that help to improve the success of treatment. —Yevgeniya Nusinovich INTRODUCTION: In vivo delivery systems (IDSs) are essential for enabling the clinical use of therapeutic agents that suffer from poor bioavailability or dose-limiting systemic toxicity. Advances in IDSs, exemplified by polymeric nanoparticles and viral vectors, have facilitated the rapid advancement of multiple therapeutic paradigms, including somatic genome editing, mRNA-based therapies, and targeted cancer treatment. However, a major and persistent limitation remains: their nonselective clearance by the body's scavenger system, which greatly reduces delivery efficiency to target tissues. Among all organs, the liver constitutes the primary site of IDS clearance, with the resident Kupffer cells (KCs) acting as the dominant scavengers that can sequester most of the administered dose. Current strategies to reduce hepatic IDS clearance primarily rely on antifouling surface modification, material redesign, KC saturation, and scavenger receptor blockade. Although these approaches have achieved partial success, substantial room for improvement remains, particularly regarding generality, safety, liver selectivity, and clinical translatability. RATIONALE: Despite extensive efforts in material and engineering optimization, limited attention has been devoted to understanding how the liver sustains its high baseline capacity to clear IDSs. Identifying the central signaling pathways that govern KC-IDS interactions would thereby enable fundamentally distinct delivery-enhancing strategies applicable to diverse IDSs. Given the intimate cross-talk between the gut microbiota and the liver, we hypothesized that a gut-liver signaling axis exists to reinforce steady-state KC phagocytosis of foreign entities, including IDSs. RESULTS: Depleting gut microbiota or blocking bacteria-sensing receptors robustly reduced hepatic clearance and enhanced delivery efficiency of diverse IDSs, regardless of their chemical composition or cargo identity. These effects translated into substantially improved efficacy of IDS-based therapies, including somatic genome editing and precision cancer therapy. The enhanced delivery efficiency was attributed to the functional deactivation of KCs, accompanied by distinct alterations in their morphology, molecular phenotype, and phagocytic activity. Gram-negative bacteria were identified as the primary drivers of this axis, but they did not act directly on KCs through bacteria-derived products. Instead, gut bacteria modulated tryptophan metabolism in the intestinal epithelium, with the epithelium-derived serotonin emerging as the key messenger linking the gut to KC-mediated IDS clearance. Serotonin signaling through specific receptors on KCs triggered cytoskeletal remodeling and upregulated of the expression of phagocytosis-associated genes, thereby broadly enhancing KC uptake of diverse IDSs. Therapeutically, transient disruption of serotonin signaling, achieved by dietary restriction of the source for serotonin production or blocking the relevant serotonin receptors, broadly enhanced IDS delivery efficiency. A brief intervention window was sufficient to achieve strong therapeutic benefits across multiple clinically relevant IDS-based therapies. CONCLUSION: This work identifies a commensal-driven gut-liver immune axis as a major regulator of IDS clearance and systemic delivery efficiency, demonstrating that long-standing barriers in drug delivery can be addressed by modulation of endogenous biological pathways. From a translational perspective, strategies targeting tryptophan metabolism or serotonin signaling offer a broadly applicable approach to improve IDS performance by reducing rapid hepatic clearance or liver toxicity, with promising implications for gene therapy, mRNA-based therapies, and precision cancer therapies. A gut-liver immune axis constrains IDS-based therapies.: Gut microbiota impairs IDS circulation by sustaining a steady-state high-level hepatic scavenging function. The intestinal epithelium transmits microbiota-derived stimuli to the liver, with serotonin as the key messenger driving KC phagocytosis of IDSs. Consequently, only a few IDSs reach target tissues, resulting in suboptimal therapeutic efficacy in diverse applications. NPs, nanoparticles; LNPs, lipid nanoparticles; PAMPs, pathogen-associated molecular patterns. [ABSTRACT FROM AUTHOR]