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Organs impose distinct transport constraints, including the blood\u2013brain barrier, renal filtration, hepatic sequestration, and pulmonary clearance. Although substantial effort has focused on engineering particle structure and surface chemistry, therapeutic performance also depends on dynamic interactions at the nano\u2013bio interface. This structured critical narrative review compares how nanoparticle design variables interact with organ-specific transport mechanisms, prioritizing mechanistic primary studies and direct clinical or regulatory evidence while preserving study-specific experimental conditions. Most review papers focus on a single disease or summarize the progress of a specific nanoparticle type. In contrast, this review addresses the heterogeneity of biological filters by proposing a barrier-specific engineering framework. We evaluate diverse high-barrier environments with distinct restrictive mechanisms and describe the strategies used to overcome them in nanoparticle design. Specifically, we focus on how matching physicochemical properties to these environments can bypass physiological constraints. Using a comparative analysis methodology, we evaluate how design parameters, including size, morphology, and surface functionalization, interact with the mechanisms of major organ systems. Applying this framework across biological barriers distinguishes study-specific relationships from potentially transferable design principles. Its clinical and translational relevance is illustrated by engineered blood\u2013brain barrier shuttles for Hunter syndrome and Alzheimer disease, lipid nanoparticle platforms for mRNA vaccination, and inhaled liposomal therapies.<\/jats:p>","DOI":"10.1063\/5.0342617","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T12:49:25Z","timestamp":1789476565000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Breaking biological barriers: Engineering nanocarriers for efficient drug and gene delivery through nano\u2013bio interfaces and biophysical design"],"prefix":"10.1063","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6868-7927","authenticated-orcid":false,"given":"Zicheng","family":"Deng","sequence":"first","affiliation":[{"name":"Phoenix Children's Research Institute, Department of Child Health, University of Arizona College of Medicine \u2013 Phoenix 1 , Phoenix, Arizona 85004,","place":["USA"]},{"name":"The Materials Science and Engineering Program, Department of Mechanical, Materials, and Industrial Engineering, College of Engineering and Applied Science, University of Cincinnati 2 , Cincinnati, Ohio 45221","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6006-8387","authenticated-orcid":false,"given":"Andrew","family":"Dunn","sequence":"additional","affiliation":[{"name":"The Materials Science and Engineering Program, Department of Mechanical, Materials, and Industrial Engineering, College of Engineering and Applied Science, University of Cincinnati 2 , Cincinnati, Ohio 45221","place":["USA"]},{"name":"Shape Therapeutics 3 , Seattle, Washington 98109,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3315-0385","authenticated-orcid":false,"given":"Daniel Q.","family":"Sun","sequence":"additional","affiliation":[{"name":"The Materials Science and Engineering Program, Department of Mechanical, Materials, and Industrial Engineering, College of Engineering and Applied Science, University of Cincinnati 2 , Cincinnati, Ohio 45221","place":["USA"]},{"name":"Division Director of Otology, Neurotology, and Skull Base Surgery\/Department of Otolaryngology \u2013 Head and Neck Surgery, University of Cincinnati College of Medicine 4 , Cincinnati, Ohio 45267,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0837-7780","authenticated-orcid":false,"given":"Donglu","family":"Shi","sequence":"additional","affiliation":[{"name":"The Materials Science and Engineering Program, Department of Mechanical, Materials, and Industrial Engineering, College of Engineering and Applied Science, University of Cincinnati 2 , Cincinnati, Ohio 45221","place":["USA"]},{"name":"Department of Biomedical Engineering, College of Engineering and Applied Science, University of Cincinnati 5 , Cincinnati, Ohio 45221,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"issue":"9","key":"2026091508491940300_c1","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1038\/nbt.3330","article-title":"Principles of nanoparticle design for overcoming biological barriers to drug delivery","volume":"33","year":"2015","journal-title":"Nat. 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