Bio‐Orthogonally Labeled Orbitals‐Hybridizing Nanozymes Induce Tissue‐Resident NK Cells for Enhanced Photo‐Immunologic Therapy of Biofilms and Preventing Secondary Infection

Abstract Biofilm‐associated infections (BAIs) pose a serious threat to public health; in particular, a reactive oxygen species (ROS)‐rich biofilm microenvironment can weaken the immunological response of antimicrobial natural killer (NK) cells. Conventional phototherapy cannot consistently inhibit the escape of planktonic bacteria from BAIs, thereby enabling persistent and recurrent infections. In this study, a thymosin β4 bio‐orthogonally labeled NK (βNK) cytomembrane is proposed to decorate PtTe 2 nanozymes (βNK@PtTe 2 ) with hyperthermia and NK cells immune re‐rousing to eliminate BAIs at all stages. Te‐doped PtTe 2 exhibits outstanding ROS scavenging activity through an electron‐enriched catalytic center with strong p‐d orbital hybridization, and it generates a thermally driven force for disorganizing dense biofilm structures under laser irradiation. After biofilm elimination and ROS scavenging, the βNK cytomembrane in βNK@PtTe 2 selectively promotes chemotaxis and activates conventional NK (cNK) cells to kill planktonic bacteria that escape from biofilm disintegration at the infection site. In vivo, this therapeutic paradigm of immune microenvironment remodeling induces cNK cells to develop into long‐lived tissue‐resident NK (trNK) cells with an immunological memory against reinvading pathogens, thereby effectively preventing secondary infections. Overall, the as‐prepared βNK@PtTe 2 combined with NK cells provides a systematic photo‐immunologic strategy to inhibit recurrent biofilms and treat infectious diseases caused by such infections.