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Although soluble ACE2 can neutralize virions, its efficacy is limited by viral load and binding affinity. Herein, we engineered smart, programmable membrane\u2010engineered nanosponges (ACNPs) displaying high\u2010density ACE2 and encapsulating the viral entry inhibitor camostat. Combining customized ACE2 receptors with camostat enforces sequential recognition and endocytosis blockade: viruses are captured through S protein\u2013ACE2 binding, followed by suppression of S protein cleavage to inhibit viral endocytosis and achieve ultra\u2010early blockade at the infection source. ACNPs exhibit an IC\n                    <jats:sub>50<\/jats:sub>\n                    that is 22\u2010fold lower than that of ACE2\u2010only nanosponges and prevent more than 99% of viral entry. After intratracheal nebulization, ACNPs persist in the lungs for over 72\u00a0h, achieving over 92% viral clearance and 80%\u2013100% survival. ACNPs also inhibit authentic HCoV\u2010NL63 infection, offering a deployable, non\u2010invasive, universal strategy for early intervention against pan ACE2\u2010dependent coronaviruses and future \u201cX viruses\u201d.\n                  <\/jats:p>","DOI":"10.1002\/advs.77592","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:14:44Z","timestamp":1789618484000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intelligent Programmable Membrane Nanosponge for Early Virus Blocking"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8168-6291","authenticated-orcid":false,"given":"Ze","family":"Chen","sequence":"first","affiliation":[{"name":"Guangdong Key Laboratory of Nanomedicine CAS\u2010HK Joint Lab of Biomaterials Institute of Biomedicine and Biotechnology Shenzhen Institutes of Advanced Technology (SIAT) Chinese Academy of Sciences  Shenzhen 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