Inflammatory environment-responsive nanomicelles targeting CD44 alleviate allergic asthma by inhibiting the TLR4/MyD88-NFκB pathway

Allergic asthma (AAS) is a chronic inflammatory airway disease. While zileuton (ZIL) has the efficient ability to relieve AAS symptoms, its systemic, untargeted administration could lead to adverse neurological effects. Thus, we constructed a drug combination nanomicelle (NMs) platform, H(BZP)-NMs, to reach synergistic effect therapy. It was comprised of a hydrophilic end formed from methoxy poly(ethylene glycol) (mPEG) and poly( L -glutamic acid) (PGlu), and a ROS/pH dual-sensitive hydrophobic core. The core was created by coupling 4-(hydroxymethyl)phenylboronic acid (HPBA) to betamethasone (BMZ). Zileuton (ZIL) was strategically loaded in the core. Hyaluronic acid (HA) functionalization further enabled CD44-targeting ability. In pathological microenvironments, the boronate ester bonds undergo responsive cleavage, causing the parallel delivery of the drugs. The slow-release profile addressed the need for rapid early-stage control and prolonged late-stage relief. In vivo, H(BZP)-NMs significantly decreased Penh values, lowered the IL-4, IL-5, IL-13, and LTB4 levels, and ameliorated airway pathological injuries. Given the molecular docking and verification of network pharmacology, these effects were associated with the dual-drug synergistic inhibition of the TLR4-MyD88-NF-κB p65 signals. Collectively, this study shows that H(BZP)-NMs are an inventive nanomedicine approach that unifies targeted delivery and extended co-release, offering promise for accurate and synergistic treatment of AAS.