Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.
Department of Thoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou 215002, China.
Sci Adv. 2024 Feb 9;10(6):eabd7904. doi: 10.1126/sciadv.abd7904. Epub 2024 Feb 7.
Effective therapeutic modalities and drug administration strategies for the treatment of chronic obstructive pulmonary disease (COPD) exacerbations are lacking. Here, mucus and biofilm dual-penetrating immunoantimicrobials (IMAMs) are developed for bridging antibacterial therapy and pro-resolving immunotherapy of COPD. IMAMs are constructed from ceftazidime (CAZ)-encapsulated hollow mesoporous silica nanoparticles (HMSNs) gated with a charge/conformation-transformable polypeptide. The polypeptide adopts a negatively charged, random-coiled conformation, masking the pores of HMSNs to prevent antibiotic leakage and allowing the nebulized IMAMs to efficiently penetrate the bronchial mucus and biofilm. Inside the acidic biofilm, the polypeptide transforms into a cationic and rigid α helix, enhancing biofilm retention and unmasking the pores to release CAZ. Meanwhile, the polypeptide is conditionally activated to disrupt bacterial membranes and scavenge bacterial DNA, functioning as an adjuvant of CAZ to eradicate lung-colonizing bacteria and inhibiting Toll-like receptor 9 activation to foster inflammation resolution. This immunoantibacterial strategy may shift the current paradigm of COPD management.
针对慢性阻塞性肺疾病 (COPD) 加重的治疗，缺乏有效的治疗方式和药物管理策略。在这里，设计了一种黏液和生物膜双重穿透免疫抗菌剂（IMAMs），以桥接 COPD 的抗菌治疗和促解决免疫治疗。IMAMs 由包裹头孢他啶（CAZ）的中空介孔硅纳米颗粒（HMSNs）构建而成，并用一种电荷/构象可转换的多肽进行封闭。该多肽采用带负电荷的无规卷曲构象，掩蔽 HMSNs 的孔，以防止抗生素泄漏，并使雾化的 IMAMs 能够有效地穿透支气管黏液和生物膜。在酸性生物膜内，多肽转化为带正电荷的刚性α螺旋，增强生物膜保留并暴露孔以释放 CAZ。同时，多肽被条件激活以破坏细菌膜并清除细菌 DNA，作为 CAZ 的佐剂，以消灭肺部定植细菌，并抑制 Toll 样受体 9 的激活以促进炎症的解决。这种免疫抗菌策略可能会改变 COPD 管理的当前模式。
