Study of the Synergistic Immunomodulatory and Antifibrotic Effects of Dual-Loaded Budesonide and Serpine1 siRNA Lipid-Polymer Nanoparticles Targeting Macrophage Dysregulation in Tendinopathy

Sandra López-Cerdá*, Giuseppina Molinaro, Rubén Pareja Tello, Alexandra Correia, Sarojinidevi Künig, Peter Steinberger, Michael Jeltsch, Jouni T. Hirvonen, Goncalo Barreto, Johannes Stöckl*, Hélder A. Santos*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Musculoskeletal diseases involving tissue injury comprise tendon, ligament, and muscle injury. Recently, macrophages have been identified as key players in the tendon repair process, but no therapeutic strategy involving dual drug delivery and gene delivery to macrophages has been developed for targeting the two main dysregulated aspects of macrophages in tendinopathy, i.e., inflammation and fibrosis. Herein, the anti-inflammatory and antifibrotic effects of dual-loaded budesonide and serpine1 siRNA lipid-polymer hybrid nanoparticles (LPNs) are evaluated in murine and human macrophage cells. The modulation of the gene and protein expression of factors associated with inflammation and fibrosis in tendinopathy is demonstrated by real time polymerase chain reaction and Western blot. Macrophage polarization to the M2 phenotype and a decrease in the production of pro-inflammatory cytokines are confirmed in macrophage cell lines and primary cells. The increase in the activity of a matrix metalloproteinase involved in tissue remodelling is proven, and studies evaluating the interactions of LPNs with T cells proved that dual-loaded LPNs act specifically on macrophages and do not induce any collateral effects on T cells. Overall, these dual-loaded LPNs are a promising combinatorial therapeutic strategy with immunomodulatory and antifibrotic effects in dysregulated macrophages in the context of tendinopathy.

Original languageEnglish
Pages (from-to)18643-18657
Number of pages15
JournalACS Applied Materials and Interfaces
Volume16
Issue number15
Early online date2 Apr 2024
DOIs
Publication statusPublished - 17 Apr 2024
MoE publication typeA1 Journal article-refereed

Keywords

  • dual drug delivery
  • lipid−polymer hybrid nanoparticles
  • macrophages
  • siRNA
  • tendinopathy

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