Sepsis, which is the most severe
clinical manifestation of acute
infection and has a mortality rate higher than that of cancer, represents
a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host
immune paralysis are the leading causes of sepsis-associated death,
but limited clinical interventions that target sepsis have failed
to effectively restore immune homeostasis to enable complete eradication
of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV
peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs
enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR)
mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion
target) siRNA to MΦs in situ, yielding CAR-MΦs
with boosted bactericidal potency. Specifically, our results demonstrated
that the engineered MΦs could efficiently phagocytose and digest
MRSA intracellularly, preventing immune evasion by the “superbug”
MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform
for multidrug-resistant (MDR) bacterial infections and should be confirmed
in clinical trials.