https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Halle (Saale) Klinik und Poliklinik für Innere Medizin III - Forschungslabor Halle (Saale), Deutschland; 2Institute of Pharmacy Halle, Deutschland; 3University Hospital Clinic for Hematology and Oncology Halle, Deutschland; 4Medizinische Klinik und Poliklinik IV Abteilung für klinische Pharmakologie München, Deutschland; 5Universitätsklinikum Halle (Saale) Klinik und Poliklinik für Innere Medizin III Halle (Saale), Deutschland; 6Universitätsspital Basel Clinic for medical oncology Basel, Schweiz
Background:
Effective modulation of post-infarction inflammation is crucial to mitigate adverse cardiac remodeling and prevent heart failure. An early switch from pro-inflammatory to a pro-healing response is desirable, without suppressing inflammation in toto. Current approaches often lack precision in targeting inflammatory networks, especially within the mononuclear phagocyte system, which plays a key role in post-infarct inflammation.
Objective:
This study investigates the biodistribution and therapeutic effects of phospholipid-liposomes – phosphatidylserine (PS), phosphatidylglycerol (PG), and phosphatidylcholine (PC) – in directing macrophage and T-cell responses post-myocardial infarction, targeting early inflammation, enhancing reparative immune-profiles, promoting cardiac healing.
Methods:
In vitro, the cytokine-profile of murine peritoneal macrophages stimulated with LPS/IFNγ was analysed by an 28-analyte bead-based multiplex assay. In vivo, experimental myocardial infarction was induced in young SKH1 outbred mice via ligation of the left descendant coronary artery. Liposomes were administered pre- and post-infarction, their biodistribution tracked over 48 hours via non-invasive fluorescence imaging, verified by immunohistochemistry. Flow cytometry analysed macrophage, dendritic cell and T cell phenotype, and sequencing T cell clonal repertoire at 72 hours post infarction. Treatment efficacy was evaluated by echocardiography.
Results:
While cytokine-analysis delineated treatment effects of each phospholipid on cultured macrophages, especially PS-liposomes significantly induced an anti-inflammatory response, marked by increased production of e.g. IL-4, IL-10 and IL-13 (p<0.05). Injected PS- and PG-liposomes exhibited rapid clearance by hepatic and splenic macrophages, while PC-liposomes displayed sustained circulation (p=0.003) and preferential accumulation within the infarct zone (p<0.001) and inflamed tissues (p<0.0001). Functionally, PC-liposomes elevated MHCII and CD206 expression in cardiac macrophages (p<0.0001 and p=0.06, respectively), suggesting an enhanced reparative phenotype. PS-liposome treatment trended to increase MHCII expression on splenic and hepatic dendritic cells, alongside with reductions in T-cell clonal diversity in mediastinal lymph nodes (p<0.03), indicating a targeted pro-healing response, ranging from the liver and spleen to heart. Notably, echocardiography revealed improvement in left ventricular function (p=0.005) in PS-treated mice already by day 2.5 post-infarction.
Conclusion:
Phospholipid liposomes offer a targeted immunomodulatory approach to improve post-infarction cardiac recovery. By selectively modulating macrophage and T-cell phenotypes, particularly through PS-liposome administration, this strategy has the potential to enhance reparative immune responses and functional recovery. These findings suggest a promising avenue for novel therapeutic interventions in myocardial infarction, with the potential for translation into clinical settings to prevent heart failure.