Phosphatidylserine liposomes for Mycobacterium abscessus infections management in people with cystic fibrosis non-eligible for CFTR modulators Tommaso Olimpieri, Noemi Poerio, Fabio Saliu, Nicola I. Lorè, Fabiana Ciciriello, Greta Ponsecchi, Federico Alghisi, Daniela M. Cirillo, Marco M. D’Andrea, Maurizio Fraziano Frontiers in Immunology, 2026 We previously demonstrated that phosphatidylserine liposomes (PS-L) reduce inflammation and enhance intracellular killing of Mycobacterium abscessus (Mab) in infected human macrophages, with functional or pharmacologically inhibited cystic fibrosis conductance regulator (CFTR). Here, we evaluated the in vitro therapeutic potential of PS-L in macrophages from people with cystic fibrosis (pwCF), either under therapeutic regimen or not with CFTR modulator therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI). Results show that PS-L exerted an anti-inflammatory effect in Mab infected macrophages, reducing TNF-α and IL-1β production and inducing IL-10 release at early and late time points, respectively. In addition, PS-L significantly increased antimycobacterial activity in macrophages from pwCF either undergoing or not ETI regimen. Importantly, in ETI-ineligible pwCF, PS-L alone still was capable to enhance a significant antimycobacterial response. Finally, PS-L combined with amikacin further enhanced intracellular bacterial clearance compared to single treatments. Altogether, these findings support PS-L as a promising host-directed therapy against Mab infection, particularly for pwCF who cannot benefit from ETI.
Phosphatidylinositol 5-Phosphate-Loaded Apoptotic Body-Like Liposomes for Mycobacterium abscessus Infection Management in Patients With Cystic Fibrosis Tommaso Olimpieri, Noemi Poerio, Fabio Saliu, Nicola I Lorè, Fabiana Ciciriello, et al. Journal of Infectious Diseases, 2025 The study investigates therapeutic strategies for managing chronic Mycobacterium abscessus infections, particularly in people with cystic fibrosis (PWCF) who are ineligible for standard elexacaftor, tezacaftor, ivakaftor (ETI) treatments. Apoptotic body-like liposomes loaded with phosphatidylinositol 5-phosphate (ABL/PI5P) were tested in vitro in M. abscessus-infected macrophages from PWCF as potential treatment. ABL/PI5P reduced intracellular bacterial viability and showed enhanced effects on a M. abscessus clinical strain when combined with amikacin. Notably, ABL/PI5P was effective on macrophages from PWCF not receiving ETI therapy. The findings suggest ABL/PI5P liposomes as a promising alternative or adjunct therapy, especially for those who cannot access ETI treatment, warranting further clinical investigation.
CPX-351 exploits the gut microbiota to promote mucosal barrier function, colonization resistance, and immune homeostasis Giorgia Renga, Emilia Nunzi, Claudia Stincardini, Marilena Pariano, Matteo Puccetti, Giuseppe Pieraccini, Claudia Di Serio, Maurizio Fraziano, Noemi Poerio, Vasileios Oikonomou, Paolo Mosci, Enrico Garaci, Luana Fianchi, Livio Pagano, Luigina Romani Blood, 2024 CPX-351, a liposomal combination of cytarabine plus daunorubicin, has been approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes, because it improves survival and outcome of patients who received hematopoietic stem cell transplant compared with the continuous infusion of cytarabine plus daunorubicin (referred to as “7 + 3” combination). Because gut dysbiosis occurring in patients with AML during induction chemotherapy heavily affects the subsequent phases of therapy, we have assessed whether the superior activity of CPX-351 vs “7 + 3” combination in the real-life setting implicates an action on and by the intestinal microbiota. To this purpose, we have evaluated the impact of CPX-351 and “7 + 3” combination on mucosal barrier function, gut microbial composition and function, and antifungal colonization resistance in preclinical models of intestinal damage in vitro and in vivo and fecal microbiota transplantation. We found that CPX-351, at variance with “7 + 3” combination, protected from gut dysbiosis, mucosal damage, and gut morbidity while increasing antifungal resistance. Mechanistically, the protective effect of CPX-351 occurred through pathways involving both the host and the intestinal microbiota, namely via the activation of the aryl hydrocarbon receptor–interleukin-22 (IL-22)–IL-10 host pathway and the production of immunomodulatory metabolites by anaerobes. This study reveals how the gut microbiota may contribute to the good safety profile, with a low infection-related mortality, of CPX-351 and highlights how a better understanding of the host-microbiota dialogue may contribute to pave the way for precision medicine in AML.
Phosphatidylserine liposomes induce a phagosome acidification-dependent and ROS-mediated intracellular killing of Mycobacterium abscessus in human macrophages Tommaso Olimpieri, Noemi Poerio, Greta Ponsecchi, Gustavo Di Lallo, Marco Maria D’Andrea, Maurizio Fraziano Frontiers in Cellular and Infection Microbiology, 2024 Mycobacterium abscessus (Mab) is an opportunistic nontuberculous mycobacterium responsible of difficult-to-treat pulmonary infections in vulnerable patients, such as those suffering from Cystic Fibrosis (CF), where it represents a major cause of morbidity and mortality. Additionally, due to the intrinsic extensive antimicrobial resistance spectrum displayed by this species and the side effects reported for some available antibiotics, the therapeutic management of such infections remains extremely difficult. In the present study, we show that phosphatidylserine liposomes (PS-L) enhance intracellular mycobacterial killing of Mab infected human macrophages with functional or pharmacologically inhibited cystic fibrosis conductance regulator (CFTR), by a mechanism involving phagosome acidification and reactive oxygen species (ROS) production. Additionally, PS-L significantly reduce proinflammatory response of Mab infected macrophages in terms of NF-kB activation and TNF-α production, irrespective of CFTR inhibition. Altogether, these results represent the proof of concept for a possible future development of PS-L as a therapeutic strategy against difficult-to-treat Mab infection.
Characterization of four novel bacteriophages targeting multi-drug resistant Klebsiella pneumoniae strains of sequence type 147 and 307 Greta Ponsecchi, Tommaso Olimpieri, Noemi Poerio, Alberto Antonelli, Marco Coppi, Gustavo Di Lallo, Mariangela Gentile, Eugenio Paccagnini, Pietro Lupetti, Claudio Lubello, Gian Maria Rossolini, Maurizio Fraziano, Marco Maria D’Andrea Frontiers in Cellular and Infection Microbiology, 2024 The global dissemination of multi-drug resistant (MDR) pathogenic bacteria requires the rapid research and development of alternative therapies that can support or replace conventional antibiotics. Among MDR pathogens, carbapenem-resistant Klebsiella pneumoniae (CR-Kp) are of particular concern due to their extensive resistance profiles, global dissemination in hospital environments, and their major role in some life-threatening infections. Phages, or some of their components, are recognized as one of the potential alternatives that might be helpful to treat bacterial infections. In this study, we have isolated and characterized four lytic bacteriophages targeting K. pneumoniae strains of Sequence Type (ST) 307 or ST147, two predominant high-risk clones of CR-Kp. Phages, designated vB_KpS_GP-1, vB_KpP_GP-2, vB_KpP_GP-4, and vB_KpP_GP-5, were isolated from sewage wastewater samples. The vB_KpS_GP-1 phage was a siphovirus unable to establish lysogeny with its host, while the other three were podoviruses. While 85.7% of K. pneumoniae strains of ST307 were selectively lysed by the phages vB_KpS_GP-1 or vB_KpP_GP-5, the other two phages were able to lyse all the tested strains of ST147 (n = 12). Phages were stable over a broad pH and temperature range and were characterized by burst sizes of 10–100 plaque forming units and latency periods of 10–50 minutes. Genome sequencing confirmed the absence of antibiotic resistance genes, virulence factors or toxins and revealed that two phages were likely members of new genera. Given their strictly lytic nature and high selectivity towards two of the major high-risk clones of K. pneumoniae, cocktails of these phages could represent promising candidates for further evaluation in in vivo experimental models of K. pneumoniae infection.
Mucoadhesive Rifampicin-Liposomes for the Treatment of Pulmonary Infection by Mycobacterium abscessus: Chitosan or ε-Poly-L-Lysine Decoration Jacopo Forte, Patrizia Nadia Hanieh, Noemi Poerio, Tommaso Olimpieri, Maria Grazia Ammendolia, Maurizio Fraziano, Maria Gioia Fabiano, Carlotta Marianecci, Maria Carafa, Federico Bordi, Simona Sennato, Federica Rinaldi Biomolecules, 2023 Mycobacterium abscessus (Mabs) is a dangerous non-tubercular mycobacterium responsible for severe pulmonary infections in immunologically vulnerable patients, due to its wide resistance to many different antibiotics which make its therapeutic management extremely difficult. Drug nanocarriers as liposomes may represent a promising delivery strategy against pulmonary Mabs infection, due to the possibility to be aerosolically administrated and to tune their properties in order to increase nebulization resistance and retainment of encapsulated drug. In fact, liposome surface can be modified by decoration with mucoadhesive polymers to enhance its stability, mucus penetration and prolong its residence time in the lung. The aim of this work is to employ Chitosan or ε-poly-L-lysine decoration for improving the properties of a novel liposomes composed by hydrogenated phosphatidyl-choline from soybean (HSPC) and anionic 1,2-Dipalmitoyl-sn-glycero-3-phosphorylglycerol sodium salt (DPPG) able to entrap Rifampicin. A deep physicochemical characterization of polymer-decorated liposomes shows that both polymers improve mucoadhesion without affecting liposome features and Rifampicin entrapment efficiency. Therapeutic activity on Mabs-infected macrophages demonstrates an effective antibacterial effect of ε-poly-L-lysine liposomes with respect to chitosan-decorated ones. Altogether, these results suggest a possible use of ε-PLL liposomes to improve antibiotic delivery in the lung.
Evaluation of phages and liposomes as combination therapy to counteract Pseudomonas aeruginosa infection in wild-type and CFTR-null models Marco Cafora, Noemi Poerio, Francesca Forti, Nicoletta Loberto, Davide Pin, Rosaria Bassi, Massimo Aureli, Federica Briani, Anna Pistocchi, Maurizio Fraziano Frontiers in Microbiology, 2022 Multi drug resistant (MDR) bacteria are insensitive to the most common antibiotics currently in use. The spread of antibiotic-resistant bacteria, if not contained, will represent the main cause of death for humanity in 2050. The situation is even more worrying when considering patients with chronic bacterial infections, such as those with Cystic Fibrosis (CF). The development of alternative approaches is essential and novel therapies that combine exogenous and host-mediated antimicrobial action are promising. In this work, we demonstrate that asymmetric phosphatidylserine/phosphatidic acid (PS/PA) liposomes administrated both in prophylactic and therapeutic treatments, induced a reduction in the bacterial burden both in wild-type and cftr-loss-of-function (cftr-LOF) zebrafish embryos infected with Pseudomonas aeruginosa (Pa) PAO1 strain (PAO1). These effects are elicited through the enhancement of phagocytic activity of macrophages. Moreover, the combined use of liposomes and a phage-cocktail (CKΦ), already validated as a PAO1 “eater”, improves the antimicrobial effects of single treatments, and it is effective also against CKΦ-resistant bacteria. We also address the translational potential of the research, by evaluating the safety of CKΦ and PS/PA liposomes administrations in in vitro model of human bronchial epithelial cells, carrying the homozygous F508del-CFTR mutation, and in THP-1 cells differentiated into a macrophage-like phenotype with pharmacologically inhibited CFTR. Our results open the way to the development of novel pharmacological formulations composed of both phages and liposomes to counteract more efficiently the infections caused by Pa or other bacteria, especially in patients with chronic infections such those with CF.
Phosphatidylcholine Liposomes Down-Modulate CD4 Expression Reducing HIV Entry in Human Type-1 Macrophages Federica De Santis, Ana Borrajo Lopez, Sara Virtuoso, Noemi Poerio, Patrizia Saccomandi, Tommaso Olimpieri, Leonardo Duca, Lucia Henrici De Angelis, Katia Aquilano, Marco Maria D’Andrea, Stefano Aquaro, Alessandra Borsetti, Francesca Ceccherini-Silberstein, Maurizio Fraziano Frontiers in Immunology, 2022 A strategy adopted to combat human immunodeficiency virus type-1 (HIV-1) infection is based on interfering with virus entry into target cells. In this study, we found that phosphatidylcholine (PC) liposomes reduced the expression of the CD4 receptor in human primary type-1 macrophages but not in CD4+ T cells. The down-regulation was specific to CD4, as any effect was not observed in CCR5 membrane expression. Moreover, the reduction of membrane CD4 expression required the Ca2+-independent protein kinase C (PKC), which in turn mediated serine phosphorylation in the intracytoplasmic tail of the CD4 receptor. Serine phosphorylation of CD4 was also associated with its internalization and degradation in acidic compartments. Finally, the observed CD4 downregulation induced by PC liposomes in human primary macrophages reduced the entry of both single-cycle replication and replication competent R5 tropic HIV-1. Altogether, these results show that PC liposomes reduce HIV entry in human macrophages and may impact HIV pathogenesis by lowering the viral reservoir.
Phosphatidylserine Liposomes Reduce Inflammatory Response, Mycobacterial Viability, and HIV Replication in Coinfected Human Macrophages Noemi Poerio, Nadia R Caccamo, Marco P La Manna, Tommaso Olimpieri, Lucia Henrici De Angelis, Marco M D’Andrea, Francesco Dieli, Maurizio Fraziano Journal of Infectious Diseases, 2022 Chronic immune activation is the key pathogenetic event of Mycobacterium tuberculosis-human immunodeficiency virus (HIV) coinfection. We assessed the therapeutic value of phosphatidylserine-liposome (PS-L) in an in vitro model of M. tuberculosis-HIV coinfection. PS-L reduced nuclear factor-κB activation and the downstream production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in bacille Calmette-Guérin-infected macrophages and of TNF-α and IL-1β in M. tuberculosis-infected and M. tuberculosis-HIV–coinfected macrophages. Importantly, a significant reduction of intracellular M. tuberculosis viability and HIV replication were also observed. These results support the further exploitation of PS-L as host-directed therapy for M. tuberculosis-HIV coinfection.
