The capsular polysaccharides of group B Streptococcus (GBS) and group A Streptococcus (GAS) are important virulence factors that mimic the common mammalian host cell surface and extracellular matrix components sialic acid (Sia) and hyaluronic acid (HA), respectively. We have studied how this molecular mimicry allows the pathogens to co-opt host immuno-regulatory Siglec receptors to downregulate the innate immune defense functions of neutrophils, macrophages, NK cells and platelets. Conversely, bacterial sialidase production (Streptococcus pneumoniae) or toxin-driven sialidase induction (Staphylococcus aureus) lead to aberrant inflammation, coagulation and platelet clearance during sepsis. These diverse bacterial strategies of host cell surface molecular mimicry, enzymatic remodeling, and membrane-damaging toxins, have prompted us to “turn the table” on the pathogens in an ongoing line of collaborative investigations with UCSD nanoengineers. Here we are developing and testing novel biomimetic nanoparticle drugs, coated with host cell membranes from RBCs, platelets and macrophages. The “nanosponge” therapeutics allow the capture and sequestration of streptococcal and staphylococcal toxins, endotoxins, and excessive host cytokines during severe pneumonia and sepsis, and lie poised for entry into human clinical trials.