Globally, there are approximately 900,000 individuals with mucormycosis, mostly in India [
1,
2]. Among those at particular risk are patients with lung diseases; neutropenic patients, such as those receiving prolonged immunosuppression for hematopoietic stem cell transplants; patients receiving long-term treatment for inflammatory diseases; and patients with diabetic ketoacidosis, COVID-19, or AIDS [
3,
4,
5,
6,
7,
8,
9,
10]. The number of reported cases of mucormycosis has increased 6- to 7-fold in the last four decades [
7], paralleling the increasing numbers of individuals on immunosuppressants and very recently COVID-19. Among the diverse Mucoromycota [
11], the genus
Rhizopus and one species in particular,
Rhizopus delemar (
R. oryzae, R. arrhizus), are responsible for 50% or more of all diagnosed cases [
7,
12,
13].
R. delemar is an opportunistic pathogen living in soil on rotting vegetation. The primary infection route is via inhalation of its sporangiospores, which leads most commonly to pulmonary and rhino-orbito-cerebral infections [
14]. Liposomal amphotericin B (AmB) followed by isavuconazole (ISZ) and/or posaconazole (POS) are the most commonly prescribed antifungals [
15]. The surgical removal of infected tissue prior to antifungal therapy significantly improves the outcome [
16,
17]. However, even with antifungal therapy and surgery, there is still approximately a 50% to 99% mortality rate within several months of diagnosis depending upon the level of dissemination at the time of accurate diagnosis and treatment [
7,
14,
16,
18]. Clearly, there is a critical need for improved antifungal therapies for mucormycosis.
The immune response to infections caused by
Rhizopus spp. is mediated by signaling from the C-type lectin pathogen receptor Dectin-1 (
CLEC7A) [
12]. Dectin-1 is expressed on the surface of some classes of leukocytes, including dendritic cells and neutrophils. Indirect evidence suggests Dectin-1 may bind directly to oligoglucans expressed by
Rhizopus [
19,
20]. Two Dectin-1 monomers float together such that their extracellular carbohydrate recognition domains (CRDs) form homo-dimers that bind with high affinity to beta-glucans in the cell wall and/or the exopolysaccharide matrices of pathogens [
21].
WThe
hresearchers have been developing DectiSomes as anti-infective agents, using C-type lectin pathogen receptors to target liposomes loaded with antifungal drugs to pathogenic fungi [
22,
23,
24].
The Weresearchers have shown that the CRD and stalk region of Dectin-1 may be tethered to liposomes loaded with antifungal drugs, targeting these liposomes specifically to beta-glucans on the surface of fungal pathogens [
23,
25]. As designed, Dectin-1 CRD monomers float in the liposomal membrane and form the functional homo-dimers necessary for beta-glucan binding. Dectin-1-coated, AmB-loaded liposomes (DEC1-AmB-LLs) bind to the cell walls and exopolysaccharides of
Aspergillus fumigatus and
Candida albicans orders of magnitude more strongly than untargeted AmBisome
®-like AmB-LLs. DEC1-AmB-LLs also inhibit and/or kill in vitro-grown
A. fumigatus 100-fold more efficiently than AmB-LLs, reducing the in vitro effective dose for 90% killing more than 10-fold. Considering that Dectin-1 might bind directly to
R. delemar,
wthe researche
rs explored the binding of DEC1-AmB-LLs to
R. delemar and their potential to enhance the efficacy of antifungal liposome treatment.