Carrier-free nanoparticles in microneedles disrupt endosomal acidification suppress ferroptosis in radiation-induced oral mucositis.

Radiation-induced oral mucositis (RIOM) is the most common complication in patients receiving radiotherapy for head and neck, to which ferroptosis is an important contributor. Transferrin receptor (TFRC) -mediated endocytosis is a critical source of iron. Accordingly, we proposed that inhibiting ferroptosis by disrupting TFRC mediated-iron uptake. In this study, we developed endosome-targeting self-assembling nanoparticles (CB NPs) integrated into a detachable microneedle patch (CBT@MNs) for precise and synergistic RIOM therapy. This system integrated the clinically conventional drugs chloroquine and baicalin and loaded into MN patch for mucosal drug delivery. In the tongue mucosa, the MN tips released CB NPs. Upon entering endosomes through the endocytosis pathway, CB NPs disrupted endosomal acidification through the proton sponge effect, which may block TFRC recycling, achieving long-term inhibition of ferroptosis and inflammation efficacy. In rat models of RIOM, CBT@MNs dramatically attenuated mucosal ulceration and accelerated healing via anti-inflammation, angiogenesis, and collagen deposition. Transcriptomic analysis further revealed that CBT@MNs suppressed ferroptosis and inflammatory signaling. This radioprotective strategy for inhibiting ferroptosis and regulating redox homeostasis provided a novel approach for designing tissue engineering materials.