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Nevertheless, developing therapy vectors crossing both biological and cellular barriers has encountered significant challenges deriving from various external factors. Herein, the rational integration of gelatin nanoparticles (GNPs) with tetrahedral DNA nanostructures (TDNs) to engineer a distinct drug\u2010delivery nanosystem (designed as TDN@GNP) efficiently enhances the biological permeability and cellular internalization, further resolving the dilemma of noise\u2010induced hearing loss via loading epigallocatechin gallate (EGCG) with anti\u2010lipid peroxidation property. Rationally engineering of TDN@GNP demonstrates dramatic alterations in the physicochemical key parameters of TDNs that are pivotal in cell\u2010particle interactions and promote cellular uptake through multiple endocytic pathways. Furthermore, the EGCG\u2010loaded nanosystem (TDN\u2010EGCG@GNP) facilitates efficient inner ear drug delivery by superior permeability through the biological barrier (round window membrane), maintaining high drug concentration within the inner ear. The TDN\u2010EGCG@GNP actively overcomes the cell membrane, exhibiting hearing protection from noise insults via reduced lipid peroxidation in outer hair cells and spiral ganglion neurons. This work exemplifies how integrating diverse vector functionalities can overcome biological and cellular barriers in the inner ear, offering promising applications for inner ear disorders.<\/jats:p>","DOI":"10.1002\/smll.202310604","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T05:57:04Z","timestamp":1707371824000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Gelatin\u2010Encapsulated Tetrahedral DNA Nanostructure Enhances Cellular Internalization for Treating Noise\u2010Induced Hearing Loss"],"prefix":"10.1002","volume":"20","author":[{"given":"Ke","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai 200100 P. R. 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