Group A Streptococcus (GAS) expresses a multitude of virulence factors with diverse modes of action that act to overcome the host’s innate immune defense mechanisms. The pore-forming toxin (PFT) streptolysin O (SLO), a well-characterized virulence factor produced by nearly all GAS clinical isolates, is necessary and sufficient to promote epithelial injury and increased pathogenicity in animal models of invasive GAS infection. In the present work, we describe two companion approaches toward novel therapeutics that block SLO-mediated toxicities. The first is through the pharmacological presentation of red blood cell (RBC)-derived biomimetic nanoparticles (“nanosponges”), which can sequester SLO and block the ability of GAS to damage host cells, preserving innate immune function and increasing bacterial clearance in vitro and in vivo. Nanosponge administration protected human neutrophils, macrophages and keratinocytes against SLO-mediated cytotoxicity, and increased GAS killing by the respective phagocytic cells. In a murine model of GAS necrotizing skin infection, local nanosponge administration was associated with decreased lesion size and reduced bacterial colony-forming unit recovery. This simple “decoy capture” platform represents a novel strategy that could prove a powerful adjunctive therapy in severe GAS infections. Our second approach employs a CRISPR-based mutagenized haploid cell genetic screen to identify novel host factors involved in mediating SLO toxicity. Through this method, we have discovered gene candidates involved in cholesterol metabolism whose reduced expression promotes resistance to SLO cytotoxicity. Individual “hits” have been validated by CRISP knockdown, and their viability as targets for drug intervention extended to models of SLO-mediated cytopathology and GAS infection.