Departments of Nanoengineering, University of California, San Diego, La Jolla, California 92093, United States.
Chemistry & Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.
Bioconjug Chem. 2022 Sep 21;33(9):1685-1697. doi: 10.1021/acs.bioconjchem.2c00305. Epub 2022 Aug 26.
Traumatic brain injury (TBI) is a major cause of disability and death among children and young adults in the United States, yet there are currently no treatments that improve the long-term brain health of patients. One promising therapeutic for TBI is brain-derived neurotrophic factor (BDNF), a protein that promotes neurogenesis and neuron survival. However, outstanding challenges to the systemic delivery of BDNF are its instability in blood, poor transport into the brain, and short half-life in circulation and brain tissue. Here, BDNF is encapsulated into an engineered, biodegradable porous silicon nanoparticle (pSiNP) in order to deliver bioactive BDNF to injured brain tissue after TBI. The pSiNP carrier is modified with the targeting ligand CAQK, a peptide that binds to extracellular matrix components upregulated after TBI. The protein cargo retains bioactivity after release from the pSiNP carrier, and systemic administration of the CAQK-modified pSiNPs results in effective delivery of the protein cargo to injured brain regions in a mouse model of TBI. When administered after injury, the CAQK-targeted pSiNP delivery system for BDNF reduces lesion volumes compared to free BDNF, supporting the hypothesis that pSiNPs mediate therapeutic protein delivery after systemic administration to improve outcomes in TBI.
创伤性脑损伤（TBI）是美国儿童和青年残疾和死亡的主要原因，但目前尚无改善患者长期大脑健康的治疗方法。一种有前途的 TBI 治疗方法是脑源性神经营养因子（BDNF），它是一种促进神经发生和神经元存活的蛋白质。然而，BDNF 的系统性递送存在突出的挑战，包括其在血液中的不稳定性、向大脑的转运能力差以及在循环和脑组织中的半衰期短。在这里，BDNF 被包裹在工程化的、可生物降解的多孔硅纳米颗粒（pSiNP）中，以便在 TBI 后将生物活性 BDNF 递送到受损的脑组织中。pSiNP 载体用靶向配体 CAQK 进行修饰，CAQK 是一种与 TBI 后上调的细胞外基质成分结合的肽。蛋白质货物在从 pSiNP 载体释放后保持生物活性，并且 CAQK 修饰的 pSiNPs 的全身给药导致蛋白质货物有效递送到 TBI 小鼠模型中的受损脑区。在损伤后给药时，与游离 BDNF 相比，CAQK 靶向的 pSiNP 递送系统用于 BDNF 可减少病变体积，支持 pSiNP 通过全身给药介导治疗性蛋白质递送以改善 TBI 结局的假说。
