Scavenger receptor–mediated lung-targeted delivery of anti-miR-155 oligoDNA nanomicelles with curcumin for acute lung injury therapy

Abstract

Antisense oligonucleotides offer a powerful strategy for suppressing pro-inflammatory microRNAs, but efficient long-term delivery after systemic administration remains challenging. In this study, we developed a self-assembling oligoDNA-nanomicelle (OD-micelle) platform to simultaneously deliver antisense oligoDNA targeting miR-155 and curcumin, a hydrophobic anti-inflammatory agent, to the lung. The curcumin formulation (OD-micelle/Cur) can be administered intravenously and has a negatively charged surface and average particle size of ∼160 nm, supporting scavenger receptor (SR)-mediated pulmonary delivery. Fluorescence imaging and flow cytometry analyses demonstrated that cellular uptake was comparable to that of OD-micelle/PEI25k, a widely used cationic carrier standard. Hemocompatibility tests demonstrated reduced red blood cell aggregation, compared with PEI25k, indicating improved hemocompatibility without compromising delivery efficiency. Mechanistic studies supported the receptor-dependent transport of the oligoDNA corona. Pre-treatment with excess oligonucleotides reduced the cellular uptake and in vivo lung accumulation of Cy5-labeled OD-micelle/Cur. Furthermore, a RAGE antagonist peptide similarly reduced cellular uptake, suggesting the involvement of RAGE in the SR pathway. In LPS-induced acute lung injury (ALI) mice and LPS-stimulated Raw264.7 cells, the OD-micelle/Cur suppressed the inflammatory response, decreased TNF-α and IL-6 levels, and improved lung histopathology. The antisense oligoDNA corona contributed to the efficacy through miR-155 inhibition, which was confirmed by comparison with scrambled OD-micelle/Cur and increased SOCS1 expression in lung tissue. Furthermore, RAGE pathway inhibition attenuated the inflammatory response, suggesting that RAGE signaling could be an additional therapeutic mechanism. Therefore, OD-micelles are a systemically administrable, lung-targeted oligonucleotide nanoplatform with dual-mechanism anti-inflammatory activity for the treatment of ALI.