In situ macrophage CAR programming via ROS-responsive microneedles enhances efferocytosis and promotes mucosal...

Area of Science:

• Biomaterials Science
• Immunology
• Regenerative Medicine

Background:

• Radiation-induced oral mucositis (RIOM) is a severe side effect of head and neck cancer radiotherapy.
• Current treatments for RIOM are inadequate for managing oxidative stress and impaired immune clearance.
• A pathological loop of reactive oxygen species (ROS), poor efferocytosis, and inflammation hinders mucosal repair in RIOM.

Purpose of the Study:

• To develop a localized, in situ therapeutic strategy for RIOM.
• To engineer a microneedle patch (PTC MN) capable of ROS-responsive drug delivery and macrophage programming.
• To investigate the potential of PTC MN in accelerating mucosal healing and resolving inflammation in RIOM.

Main Methods:

• Fabrication of a ROS-responsive microneedle patch (PTC MN) using a PPBA-TA-PVA hydrogel.
• Loading the patch with engineered hybrid nanovesicles (HLENs-CAR) carrying a CAR-ectoCRT-IL-4 plasmid for macrophage programming.
• Evaluation of PTC MN efficacy in a murine RIOM model, assessing mucosal regeneration, oxidative stress, inflammation, and macrophage function.

Main Results:

• PTC MN accelerated mucosal epithelial regeneration and reduced oxidative stress and inflammatory infiltration in the RIOM model.
• The microneedle patch enhanced macrophage efferocytosis and promoted reparative macrophage polarization (IL-4 associated).
• PTC MN treatment shifted the lesion microenvironment towards inflammation resolution and tissue regeneration, attenuating fibrosis.

Conclusions:

• The developed ROS-responsive microneedle patch (PTC MN) offers a smart in situ immunomodulation strategy for RIOM.
• This approach integrates ROS-responsive delivery with targeted macrophage programming for enhanced mucosal repair.
• PTC MN represents a potential therapeutic paradigm for refractory mucosal injuries like RIOM.