Neuropathic pain caused by nerve injury is debilitating and difficult to treat. Current systemic pharmacological therapeutics for neuropathic pain produce limited pain relief and have undesirable side effects, while current local anesthetics tend to nonspecifically block both sensory and motor functions. Calcitonin gene related peptide (CGRP), a neuropeptide released from sensory nerve endings, appears to play a significant role in chronic neuropathic pain. In this study, an analgesic microneedle (AMN) patch was developed using dissolvable microneedles to transdermally deliver selective CGRP antagonist peptide in a painless manner for the treatment of localized neuropathic pain. Local analgesic effects were evaluated in rats by testing behavioral pain sensitivity in response to thermal and mechanical stimuli using neuropathic pain models such as spared-nerve injury and diabetic neuropathy pain, as well as neurogenic inflammatory pain model induced by ultraviolet B (UVB) radiation. Unlike several conventional therapies, the AMN patches produced effective analgesia on neuropathic pain without disturbing the normal nociception and motor function of the rat, resulting from the high specificity of the delivered peptide against CGRP receptors. The AMN patches did not cause skin irritation or systemic side effects. These results demonstrate that dissolvable microneedle patches delivering CGRP antagonist peptide provide an effective, safe, and simple approach to mitigate neuropathic pain with significant advantages over current treatments.
nanotopographies optimized to facilitate biomolecular delivery, genome editing, and cellular modulation-have enormous potential to build capacity over a range of collaborating disciplines associated with biomedical research. High-aspect-ratio nanostructures are now providing major advantages in precise manipulation of increasingly complex cellular processes, assisting the translation into clinical applications such as tissue engineering, regenerative medicine, drug delivery, biosensing, and cancer immunotherapies. [2-5] In particular, 1D vertical nanostructures (1D-VNS)-nanowires, nanoneedles, nanopillars, nanotubes, nanosyringes, nanostraws, nanocones, and nanospikes (Figure 1a)-have helped tackle various biological problems such as intracellular recording and genetic interrogation. [6-16] Unlike other highaspect-ratio nanostructures, such as freestanding carbon nanotubes, 1D-VNS can be rationally designed and synthesized, via top-down and/or bottom-up approaches, with defined key parameters-including topological geometry (pitch, diameter, length), chemical composition, doping, and electronic propert ies. [17-21] So by well-controlled programming coupled with selective surface functionality, 1D-VNS can provide unprecedented spatial and mechanical resolution to enable direct, Engineered nano-bio cellular interfaces driven by 1D vertical nanostructures (1D-VNS) are set to prompt radical progress in modulating cellular processes at the nanoscale. Here, tuneable cell-VNS interfacial interactions are probed and assessed, highlighting the use of 1D-VNS in immunomodulation, and intracellular delivery into immune cells-both crucial in fundamental and translational biomedical research. With programmable topography and adaptable surface functionalization, 1D-VNS provide unique biophysical and biochemical cues to orchestrate innate and adaptive immunity, both ex vivo and in vivo. The intimate nanoscale cell-VNS interface leads to membrane penetration and cellular deformation, facilitating efficient intracellular delivery of diverse bioactive cargoes into hard-to-transfect immune cells. The unsettled interfacial mechanisms reported to be involved in VNS-mediated intracellular delivery are discussed. By identifying up-to-date progress and fundamental challenges of current 1D-VNS technology in immune-cell manipulation, it is hoped that this report gives timely insights for further advances in developing 1D-VNS as a safe, universal, and highly scalable platform for cell engineering and enrichment in advanced cancer immunotherapy such as chimeric antigen receptor-T therapy.
Autophagy dysfunction is a potential toxic effect of nanoparticles. Previous studies have indicated that silica nanoparticles (SiNPs) induce macroautophagy/autophagy dysfunction, while the precise mechanisms remain uncertain. Hence, the present study investigated the molecular mechanisms by which SiNPs enhanced autophagosome synthesis, which then contributed to autophagy dysfunction. First, the effects of SiNPs on autophagy and autophagic flux were verified using transmission electron microscopy, laser scanning confocal microscopy, and western blot assays. Then, the activation of endoplasmic reticular (ER) stress was validated to be through the EIF2AK3 and ATF6 UPR pathways but not the ERN1-XBP1 pathway, along with the upregulation of downstream ATF4 and DDIT3. Thereafter, the ER stress inhibitor 4-phenylbutyrate (4-PBA) was used to verify that SiNP-induced autophagy could be influenced by ER stress. Furthermore, specialized lentiviral shRNA were employed to determine that autophagy was induced via specific activation of the EIF2AK3 and ATF6 UPR pathways. Finally, the 2 autophagic genes LC3B and ATG12 were found to be transcriptionally upregulated by downstream ATF4 and DDIT3 in ER stress, which contributed to the SiNP-enhanced autophagosome synthesis. Taken together, these data suggest that SiNPs induced autophagosome accumulation via the activation of the EIF2AK3 and ATF6 UPR pathways in hepatocytes, which offers a new insight into detailed molecular mechanisms underlying SiNP-induced autophagy dysfunction, and specifically how UPR pathways regulate key autophagic genes. This work provides novel evidence for the study of toxic effects and risk assessment of SiNPs.
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