Invasive fungal diseases (IFDs) cause millions of deaths each year and they are refractory to treatment. Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Rhizopus oryzae cause life- threatening invasive candidiasis, pulmonary aspergillosis, cryptococcal meningitis, and murormycosis, respectively. Patients at the greatest risk of developing these IFDs have weakened immune systems such as HIV positive individuals. The vulnerable population is increasing due to increasing numbers of immunosuppressed individuals receiving stem cell or organ transplants. In the U.S. medical costs for these three IFDs exceed $5 billion dollar per year. An infected individual’s medical cost often exceed $100,000. Patients are treated with various antifungal drugs, but all antifungals have serious limitations due to human organ toxicity, the lack of sufficient fungicidal effect at safe doses and safely limited treatment periods, and the emergence of resistant fungi. Even with treatment, one-year survival is only 1% to 90%, depending upon the patient population. Few new drugs have gained acceptance in the last 20 years. We created a transformative technology in which almost any antifungal drug may be delivered specifically to the fungal cell wall and/or their secreted exopolysaccharide matrices to increase drug efficacy by orders of magnitude. This technology and the conceptual framework supporting it meet the critical need for dramatically improved antifungal therapeutics. We have employed the carbohydrate recognition domains of the C-type lectin receptors Dectin-1 and Dectin-2 to target liposomal packaged antifungals to fungal glucans and mannans. Antifungals such as Amphotericin B packaged in liposome penetrate the endothelium, have longer half-lives and less infusion toxicity than detergent solubilized drugs. We have remarkably strong in vitro data showing that Dectin-1- and/or Dectin-2-targeting of Amphotericin B-loaded liposomes improved binding efficiency to these four diverse fungal species 100-fold over untargeted liposomes and killed three species 10- to 100-times more efficiently. The deliverables of this high-risk high-reward proposal include (1) demonstrating that Dectin-3 in combination the other Dectins expands fungal cell targeting capabilities, (2) generalizing the technology to the delivery of other antifungals agents such as fluconazole and anidulafungin, and (3) assembling a preclinical data package showing that targeted antifungal-loaded liposomes have increased efficacy in mouse models of invasive candidiasis, pulmonary aspergillosis, cryptococcal meningitis, and pulmonary mucormycosis. We believe we will create a paradigm shift in the antifungal pharmaceutical industry. We have an established team of scientists already combining their expertise in diverse areas of science necessary to carry out these experiments. We have developed an experimental platform to rapidly innovate and reiteratively test fungal cell specific targeting...