As a typical human pathogenic fungus,Cryptococcus neoformans is a life-threatening inva-sive fungal pathogen with a worldwide distribution causing ～ 700,000 deaths annually.Cryptococcosis is not just an infection with multi-organ involvement,intracellular survival and extracellular multiplication of the fungus also play important roles in the pathogenesis of C.neoformans infections.Because adequate accumulation of drugs at target organs and cells is still difficult to achieve,an effective delivery strategy is desperately required to treat these infections.Here,we report a bioresponsive micro-to-nano (MTN) sys-tem that effectively clears the C.neoformans in vivo.This strategy is based on our in-depth study of the overexpression of matrix metalloproteinase 3 (MMP-3) in infectious microenvironments (IMEs) and secreted protein acidic and rich in cysteine (SPARC) in several associated target cells.In this MTN sys-tem,bovine serum albumin (BSA,a natural ligand of SPARC) was used for the preparation of nanopar-ticles (NPs),and then microspheres were constructed by conjugation with a special linker,which mainly consisted of a BSA-binding peptide and an MMP-3-responsive peptide.This MTN system was mechan-ically captured by the smallest capillaries of the lungs after intravenous injection,and then hydrolyzed into BSA NPs by MMP-3 in the IMEs.The NPs further targeted the lung tissue,brain and infected mac-rophages based on the overexpression of SPARC,reaching multiple targets and achieving efficient treat-ment.We have developed a size-tunable strategy where microspheres “shrink” to NPs in IMEs,which effectively combines active and passive targeting and may be especially powerful in the fight against complex fungal infections.