Chemotherapy‐induced neuropathic pain (CINP) is a common adverse effect of antineoplastic drugs, often leading to dose reduction, treatment delays, or cessation of chemotherapy. Chemotherapy agents, like paclitaxel (PTX), damage the somatosensory nervous system by inducing neuroinflammation and oxidative stress, resulting in the sensitization of sensory neurons. Quercetin (QCT), known for its anti‐inflammatory, antioxidant, and neuroprotective properties, is investigated for various neurological disorders. This work creates phenylboronic acid‐modified hyaluronic acid (HA‐PBA) gels with incorporated QCT and fabricates a double‐layer microneedle (MN) patch using an HA‐PBA‐QCT complex in the needles and HA/polyvinyl alcohol (PVA) as the substrate. The crosslinking between PVA and HA‐PBA‐QCT enables a controlled, sustained release of QCT upon application. This work applies these QCT‐loaded microneedle (QMN) patches to the instep skin of PTX‐treated mice, which exhibits mechanical allodynia and cold hyperalgesia. Biweekly applications of the QMN patches significantly reduce pain responses. This analgesic effect is associated with the modulation of satellite glial cell activity, decreased macrophage infiltration, and reduced TNF‐α and IL‐6 levels in dorsal root ganglia (DRGs). Additionally, the treatment improves cellular antioxidant capacity, indicated by upregulated Nrf2 and catalase in DRGs. Overall, these findings suggest that double‐layer QMN patches offer long‐term anti‐inflammatory and antioxidant benefits, potentially alleviating CINP in patients.

The administration of therapeutics to peripheral nerve tissue is challenging due to the complexities of peripheral neuroanatomy and the limitations imposed by the blood–nerve barrier (BNB). Therefore, there is a pressing need to enhance delivery effectiveness and implement targeted delivery methods. Recently, erythrocyte-derived exosomes (Exos) have gained widespread attention as biocompatible vehicles for therapeutics in clinical applications. However, engineering targeted Exos for the peripheral nervous system (PNS) is still challenging. This study aims to develop a targeted Exo delivery system specifically designed for presynaptic terminals of peripheral nerve tissue. The clostridium neurotoxin, tetanus toxin-C fragment (TTC), was tethered to the surface of red blood cell (RBC)-derived Exos via a facile and efficient bio-orthogonal click chemistry method without a catalyst. Additionally, Cyanine5 (Cy5), a reactive fluorescent tag, was also conjugated to track Exo movement in both in vitro and in vivo models. Subsequently, Neuro-2a, a mouse neuronal cell line, was treated with dye-labeled Exos with/without TTC in vitro, and the results indicated that TTC-Exos exhibited more efficient accumulation along the soma and axonal circumference, compared to their unmodified counterparts. Further investigation, using a mouse model, revealed that within 72 h of intramuscular administration, engineered TTC-Exos were successfully transported into the neuromuscular junction and sciatic nerve tissues. These results indicated that TTC played a crucial role in the Exo delivery system, improving the affinity to peripheral nerves. These promising results underscore the potential of using targeted Exo carriers to deliver therapeutics for treating peripheral neuropathies.

Background/Objectives: Chemotherapy-induced neuropathic pain (CINP) represents a critical challenge in oncology, emerging as a common and debilitating side effect of widely used chemotherapeutic agents, such as paclitaxel (PTX). Current therapeutic interventions and preventive strategies for CINP are largely insufficient, as they fail to address the underlying peripheral nerve damage, highlighting an urgent need for the development of new drugs. This study aimed to investigate the dual-function effects on normal cell protection and tumor suppression of BMX-001, a redox-active manganese metalloporphyrin that has demonstrated antioxidant and anti-inflammatory properties, which offers potential in protecting central nervous system tissues and treating CINP. Methods: This study assessed BMX-001’s different roles in protecting normal cells while acting as a pro-oxidant and pro-inflammatory molecule in cancer cells in vitro. We also evaluated its neuroprotective effect in preclinical PTX-induced CINP models in vivo. Results: Our results showed significant reductions in mechanical and cold allodynia, decreased pro-inflammatory cytokine levels, and restored antioxidant capacity in peripheral nerves and dorsal root ganglia (DRGs) following BMX-001 treatment. Conclusions: Overall, our study highlights the therapeutic potential of BMX-001 to mitigate CINP and enhance anticancer efficiency. Its dual-selective mechanism supports the future clinical investigation of BMX-001 as a novel adjunct to chemotherapeutic regimens.