Cascade-targeting polymeric particles eliminate intracellular C. neoformans in fungal infection therapy.

C. neoformans , a life-threatening invasive fungal pathogen, can hijack the pulmonary macrophages as 'Trojan horse', leading to cryptococcal meningitis and recurrence. Combatting these elusive fungi has posed a long-standing challenge. Here, we report an inhaled cascade-targeting drug delivery platform that can sequentially target host cells and intracellular fungi. The delivery system involves encapsulating amphotericin B (AMB) into polymeric particles decorated with AMB, creating a unique surface pattern, denoted as APP@AMB. The surface topology of APP@AMB guides the efficient macrophages internalization and intracellular drugs accumulation. Following endocytosis, the surface-functionalized AMB specifically targets intracellular fungi by binding to ergosterol in the fungal membrane, as demonstrated through co-localization studies using confocal microscopy. Through on-site AMB delivery, APP@AMB displays superior efficacy in eliminating C. neoformans in the lungs and brain compared to free AMB following inhalation in infected mice. Additionally, APP@AMB significantly alleviates the nephrotoxicity associated with free AMB inhalation therapy. Thus, this biocompatible delivery system enabling host cells and intracellular fungi targeting in a cascade manner, provides a new avenue for the therapy of fungal infection. [Display omitted] • This study developed inhaled polymer particles for the delivery of Amphotericin B in the treatment of fungal infections. • The unique topology and ligand facilitate targeted delivery of AMB for treating cryptococcus intracellular infections. • The results demonstrate the potential for eradicating intracellular fungi through cascade-targeting delivery of AMB. [ABSTRACT FROM AUTHOR]