Intelligent Programmable Membrane Nanosponge for Early Virus Blocking

ABSTRACT 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 IC 50 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”.