Bacterial resistance to antibiotics has made it necessary to resort to antibiotics that have considerable toxicities. Here, we show that the cyclic 9-amino acid peptide CARGGLKSC (CARG), identified via phage display on Staphylococcus aureus (S. aureus) bacteria and through in vivo screening in mice with S. aureus-induced lung infections, increases the antibacterial activity of CARG-conjugated vancomycin-loaded nanoparticles in S. aureus-infected tissues and reduces the needed overall systemic dose, minimizing side effects. CARG binds specifically to S. aureus bacteria but not Pseudomonas bacteria in vitro, selectively accumulates in S. aureus-infected lungs and skin of mice but not in non-infected tissue and Pseudomonas-infected tissue, and significantly enhances the accumulation of intravenously injected vancomycin-loaded porous silicon nanoparticles bearing the peptide in S. aureus-infected mouse lung tissue. The targeted nanoparticles more effectively suppress staphylococcal infections in vivo relative to equivalent doses of untargeted vancomycin nanoparticles or of free vancomycin. The therapeutic delivery of antibiotic-carrying nanoparticles bearing peptides targeting infected tissue may help combat difficult-to-treat infections.

Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries.

A single-step procedure to simultaneously load and protect high concentrations of siRNA in porous silicon nanoparticles (pSiNPs) is presented. Treatment of pSiNPs with an aqueous solution containing siRNA and calcium chloride generates core-shell nanostructures consisting of an siRNA-loaded pSiNP core infiltrated with an insoluble shell of calcium silicate (Ca-pSiNPs). The source of silicate in the shell derives from local dissolution of the pSi matrix, and in solutions containing high concentrations of calcium (II) ion, Ca2SiO4 formation occurs primarily at the nanoparticle surface and is self-limiting. The insoluble calcium silicate shell slows the degradation of the pSiNP skeleton and prolongs delivery of the siRNA payload, resulting in more effective gene knockdown in vitro. Formation of the calcium silicate shell results in an increase in the external quantum yield of photoluminescence from the porous silicon core from 0.1 to 21 %, presumably due to the electronically passivating nature of the silicate shell. Attachment of two functional peptides that incorporate a sequence derived from the rabies virus glycoprotein (RVG) as a neuronal targeting peptide and myristoylated transportan (mTP) as a cell penetrating moiety to the Ca-pSiNPs yields a construct that shows improved gene silencing in vitro and improved delivery in vivo.