Preventing acute lung injury from progressing to pulmonary fibrosis by maintaining ERS homeostasis through a multistage targeting nanomicelle

Acute lung injury / acute respiratory distress syndrome (ALI/ARDS) or pulmonary fibrosis (PF) has been regarded as a global health issue with high mortality and limited drug therapy. Clinical evidence suggests that undesired macrophage polarization (M) is the main factor driving the development of ALI/ARDS, and endoplasmic reticulum stress (ERS) has been considered an important determinant of M polarization. Accordingly, we proposed a hypothesis that restoration of ER homeostasis would effectively balance the homeostasis of M and prevent ALI from progressing to pulmonary fibrosis (PF). To this end, we designed a multistage targeted nanomicelle mainly based on hyaluronic acid (HA) and alpha-tocopherol succinate (alpha-TOS) (named as HSST or pHSST with peptide modified) to load ERS inhibitor (KIRA6, K) and anti-inflammatory drug (Dexamethasone, Dex) respectively. When inflammation occurred, K-loaded pHSST (K@pHSST) and Dex-loaded HSST (Dex@HSST) firstly achieved lung targeting by "hitchhiking " myeloid M and neutrophils (Neu) that patrol in the blood and then achieved inflammation-associated cells targeting through a CD44 receptor-ligand-mediated mode by HA. For K@pHSST, at the same time, the ER-targeting molecule (Pardaxin, Par) was used to modify the nanomicelles for tertiary ER-targeting effect and specifically deli-vering of the K to ER. While in response to high-level intracellular reactive oxygen species (ROS), Dex@HSST disintegrated due to the reductive alpha-tocopherol succinate (alpha-TOS) and disulfide bond. The released Dex exerted anti-inflammatory effects and promoted type 2 M cells (M2) polarization via activating intracellular glucocorticoid receptors. Through the combined administration of Dex@HSST and K@pHSST, this strategy could effectively reduce ROS, limit cytokine storm, restore ER homeostasis, reverse imbalanced M polar-ization, and fundamentally resolve ALI and prevent PF. (c) 2022 Elsevier Ltd. All rights reserved.