Intelligent Programmable Membrane Nanosponge for Early Virus Blocking.

Coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV), and human coronavirus NL63 (HCoV-NL63), infect host cells through spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Although soluble ACE2 can neutralize virions, its efficacy is limited by viral load and binding affinity. Herein, we engineered smart, programmable membrane-engineered nanosponges (ACNPs) displaying high-density 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-ACE2 binding, followed by suppression of S protein cleavage to inhibit viral endocytosis and achieve ultra-early blockade at the infection source. ACNPs exhibit an IC50 that is 22-fold lower than that of ACE2-only nanosponges and prevent more than 99% of viral entry. After intratracheal nebulization, ACNPs persist in the lungs for over 72 h, achieving over 92% viral clearance and 80%-100% survival. ACNPs also inhibit authentic HCoV-NL63 infection, offering a deployable, non-invasive, universal strategy for early intervention against pan ACE2-dependent coronaviruses and future "X viruses".