Abella-López Daniel, López-Teijeiro Adrián, Pose-Boirazian Tomás, Barreiro-Piñeiro Natalia, Martínez-Costas José M
Department of Biochemistry and Molecular Biology and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, C/ Jerónimo de la Fuente S/N, 15782, Santiago de Compostela, Spain.
Mater Today Bio. 2025 Jun 15;33:101987. doi: 10.1016/j.mtbio.2025.101987. eCollection 2025 Aug.
Phenylketonuria (PKU) is a genetic metabolic disorder caused by an enzyme deficiency that leads to the accumulation of phenylalanine, which can cause neurotoxicity and several other problems. A potential alternative to the universal standard treatment based on a lifelong protein-restricted diet, is the development of oral replacement therapies using phenylalanine ammonia lyase from (AvPAL). However, oral administration of polypeptides presents a major challenge due to gastrointestinal (GI) instability. To address this issue, the use of the IC-Tagging system as an advanced one step, nanosphere (NS)-encapsulation strategy for protein stabilization and oral delivery is proposed. A highly active version of AvPAL was produced to which nanoencapsulation provides formidable thermostability, resistance to acidic pH, long-term storage stability and protection against proteolytic degradation. This latter characteristic, essential for oral delivery of polypeptides, is further enhanced by coating with chitosan the NS-encapsulated enzyme. Thus, a similarly nanoencapsulated and chitosan-coated luciferase displays sustained enzymatic activity through the entire GI transit when administered orally in mice, indicating the high protective capability of the system while maintaining the availability of the enzyme. Overall, these results highlight the potential and versatility for peptide-based oral delivery applications of this innovative methodology.
苯丙酮尿症（PKU）是一种由酶缺乏引起的遗传性代谢紊乱疾病，会导致苯丙氨酸积累，进而引发神经毒性及其他多种问题。基于终身蛋白质限制饮食的通用标准治疗方法的一种潜在替代方案，是开发使用来自 （AvPAL）的苯丙氨酸解氨酶的口服替代疗法。然而，由于胃肠道（GI）不稳定性，口服多肽存在重大挑战。为解决这一问题，提出使用IC标记系统作为一种先进的一步法纳米球（NS）包封策略，用于蛋白质稳定化和口服递送。制备了一种高活性版本的AvPAL，纳米包封赋予其强大的热稳定性、耐酸性pH、长期储存稳定性以及抗蛋白水解降解能力。对于多肽的口服递送至关重要的后一种特性，通过用壳聚糖包被NS包封的酶得到进一步增强。因此，当在小鼠中口服给药时，一种类似纳米包封且壳聚糖包被的荧光素酶在整个胃肠道转运过程中显示出持续的酶活性，表明该系统具有很高的保护能力，同时保持了酶的有效性。总体而言，这些结果突出了这种创新方法在基于肽的口服递送应用中的潜力和多功能性。
