**1. Introduction**

Histoplasmosis is the most common respiratory fungal disease and displays the highest endemicity in North and South America [1, 2]. Nonetheless, tourism and migration have stimulated the worldwide growth of histoplasmosis in nonendemic areas, for instance, China, South Africa, India, and Southeast Asia [3, 4]. This disease triggers symptoms and signs, such as fever, weight loss, headache, abdominal pain, chills, fatigue, chest discomfort, diarrhea, and dry cough [5–7].

The infection is caused by inhaling aerosols that contain the infecting particles of the dimorphic fungus, *Histoplasma capsulatum* and it affects most frequently the lung [8]. Nevertheless, it can also affect the skin [9–11], and the central nervous system (CNS) causing meningitis [12] or even evolve into a progressive disseminated infection that may trigger an inflammatory response and bring rheumatological and heart complications (pericarditis), with high morbidity rates [13, 14].

Upon spores' inhalation, the mycelial form goes through a dimorphic transition to yeast to infiltrate the host macrophages in almost any organ, granting its intracellular replication and survival [15–17]. Researchers have proved that the *H. capsulatum* yeasts facility on colonizing and adhering to different organ cryosections (lung, spleen, liver, gut, and trachea) is due to a well-known survival strategy of microorganisms: biofilm formation [18–20].

The at-risk population includes immunocompromised patients or those under immunosuppressive or biological regimens, as well as workers with occupational exposure to spore-laden soil [21].

The disease severity spectrum ranges from asymptomatic or mild lung disease to severe pneumonitis with respiratory compromise, depending on inoculum amount, exposure intensity, and host's immunity [9, 14, 15].

Acute or chronic systemic disease may occur and is associated with immunodepression, particularly acquired immunodeficiency syndrome (AIDS) [3]. In fact, disseminated histoplasmosis among AIDS patients is a rapidly progressing, lifethreatening illness that requires prompt treatment with antifungal medication [6]. In Latin America, histoplasmosis is often listed as the number one death cause in patients with advanced AIDS [15].

Infectious diseases caused by intracellular microorganisms, such as histoplasmosis, are described as capable of altering host defense mechanisms and hence allowing these microorganisms to survive inside mononuclear phagocytes, such as macrophages and dendritic cells [22]. These kinds of diseases are regarded as medical challenges due to drug–drug interactions during coinfections and resistance emergencies, which evidently narrows available therapies [23].

Currently, the gold standard treatment for moderate-to-severe disseminated histoplasmosis is liposomal amphotericin B (L-AmB) [1, 6]. The liposomal formulation is preferred to the conventional deoxycholate one, due to decreased nephrotoxicity, lower mortality rates in HIV patients, and overall improved clinical success [3, 24].

On the other hand, for mild and moderate forms of infection, the most appropriate choice is itraconazole. Alternatives to itraconazole include posaconazole, fluconazole, ketoconazole, and voriconazole [1, 13].

Considering the hepatoxicity, limited efficacy due to deficient absorption, low bioavailability, drug degradation, long treatment duration, and frequent drug interactions of the traditional antifungal drugs, it is imperative to develop more efficient strategies for this disease, which would be able to overcome these hurdles [8].

The functionalization of nanocarriers for drug delivery has been ceaselessly disclosing its potential as an alternative and versatile technological platform for the management and treatment of intracellular infections caused by fungi from the *H. capsulatum* species [23, 25]. Indeed, the encapsulation of antifungal agents into nanoparticles to selectively target pathogens has shed light on improving treatment's efficacy and efficiency [8]. Some of these novel drug delivery approaches, such as AmBisome® and Visudyne®, are already commercialized and now serve as benchmark treatments and proof-of-concept of the usefulness of nanotechnology in antifungal drug delivery [26–28].

However, between clear written clinical guidelines and actual clinical practice, there is sometimes a huge gap. In Latin America, for instance, the frequent lack of physician awareness about histoplasmosis and the shortage of accessible diagnostic methods translates into thousands of annual deaths amid advanced-HIV patients, which could have been prevented. It is likewise important to stress that the feasibility of implementing some of these novel treatment options, along with the therapeutic drug monitoring that they require, greatly depends on resource availability, which tends to be scarce in impoverished settings [5, 6].
