Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus

• Published in: Nature communications 2018-05, Vol.9 (1), p.1969-13, Article 1969
• Main Authors: Kim, Byungji, Pang, Hong-Bo, Kang, Jinyoung, Park, Ji-Ho, Ruoslahti, Erkki, Sailor, Michael J.
• Format: Article
• Language: English
• Subjects: 42/41; 42/89; 631/61/2300/1851; 631/61/350/354; 639/925/352/152; 692/699/255/1318; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Cytokines - immunology; Cytokines - metabolism; Cytosol; Disease Models, Animal; Drug Resistance, Bacterial - genetics; Endocytosis; Excretion; Gene Knockdown Techniques; Gene therapy; Gene transfer; Genetic Therapy - adverse effects; Genetic Therapy - methods; Homing; Humanities and Social Sciences; Humans; Immune clearance; Immune system; Immunotherapy; Inflammation; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - immunology; Liposomes; Lysosomes; Macrophages; Macrophages - drug effects; Macrophages - immunology; Male; Mice; Mice, Inbred BALB C; Molecular chains; multidisciplinary; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Oligonucleotides; Peptides; Peptides, Cyclic - administration & dosage; Pneumonia, Staphylococcal - immunology; Pneumonia, Staphylococcal - microbiology; Pneumonia, Staphylococcal - mortality; Pneumonia, Staphylococcal - therapy; Porous silicon; RAW 264.7 Cells; RNA Interference - immunology; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Science; Science (multidisciplinary); Staphylococcus aureus - drug effects; Staphylococcus aureus - physiology; Survival Analysis; Therapy; Treatment Outcome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04390-7

The incidence of adverse effects and pathogen resistance encountered with small molecule antibiotics is increasing. As such, there is mounting focus on immunogene therapy to augment the immune system’s response to infection and accelerate healing. A major obstacle to in vivo gene delivery is that the primary uptake pathway, cellular endocytosis, results in extracellular excretion and lysosomal degradation of genetic material. Here we show a nanosystem that bypasses endocytosis and achieves potent gene knockdown efficacy. Porous silicon nanoparticles containing an outer sheath of homing peptides and fusogenic liposome selectively target macrophages and directly introduce an oligonucleotide payload into the cytosol. Highly effective knockdown of the proinflammatory macrophage marker IRF5 enhances the clearance capability of macrophages and improves survival in a mouse model of Staphyloccocus aureus pneumonia. In the context of increasing bacterial antibiotic-resistance, gene therapy that targets the immune system to clear infection is a major goal. Here the authors show a silicon based nanosystem that modulates the macrophage response in an in vivo model of Staphylococcal pneumonia.