Table 1. Unmet needs in infectious disease treatment.

These are broken down into several sub-categories, with future areas of innovation to address each need.

Need	What it is	Current drug delivery limitations	Opportunities for drug development	Notable Examples
Multidrug-Resistant Organisms	Bacteria that have developed resistance to many antimicrobial drugs.	Non-targeted antibiotic delivery promotes resistance in the normal microbiota[45] Bacterial membrane changes alter antibiotic permeability[46]	Development of new classes of antibiotics Combination antibiotics within one particle Bacterial ligand-targeted antibiotic delivery Antimicrobial heavy metals and peptides	Ghosh et al. show the mixed ligand analog of the natural Acinetobacter baumannii selective siderophore coupled to daptomycin, a Gram-positive only antibiotic, resulted in antibacterial activity against multidrug resistant strains of A. baumannii both in vitro and in vivo[47].
Viruses	Infectious microorganism that needs a host living cell to replicate.	Viruses are intracellular and utilize host cell machinery for replication Much of the pathology and morbidity seen from viral infection is a function of the host immune response[48][49]	Direct-acting antivirals Modifying host factors, such as those required for viral replication, but dispensable for the host Modifying host immune response (see below)	Cao et al. reported that gold nanoparticles could be functionalized with RNAse A and then modified with anti-HCV oligonucleotides to effectively mimic the function of the cellular RNA-induced silencing complex machinery for guiding target RNA cleavage[50].
Chronic Infection	A bacterial or viral infection that is resistant to treatment or has slow growth rates, resulting in long-term infection.	Frequently these infections are in body spaces and cavities (i.e. blocked alveoli, bone, CNS) that get incomplete drug delivery via systemic administration[51] The slow growth of these bacteria requires prolonged exposure to bacteriostatic or bactericidal levels of antibiotic[52]	Combination therapy with multiple routes of antimicrobial administration, i.e. combine intravenous and inhaled treatments Nanoparticle drug depot Antiviral opportunities as above	Dou et al. demonstrated a depot-style release of indinavir, an antiretroviral drug, from macrophages over 14 continuous days which suppressed viral load significantly in the brain after intravenous administration in an HIV-1 encephalitis mouse model[53].
Emerging Pathogens	Infectious diseases that have newly appeared in a population or have existed, but are rapidly increasing in incidence or geographic range.	These pathogens also infect body spaces that are difficult for systemically administered antibiotics to reach Emerging pathogens can have resistance to the current available antibiotics[54]	Antimicrobial heavy metals and peptides Microorganism ligand-targeted anti-infective delivery	Lok et al. showed that ~9nm spherical Ag nanoparticles were able to exert antibacterial effects through destabilizing the outer membrane, collapsing the plasma membrane potential and depleting the levels of intracellular ATP[55].
Biofilms	Surface-attached microbes enclosed in an extracellular polymeric substance matrix. Biofilms are commonly seen on teeth and foreign bodies (i.e. catheters, replacement heart valves, joint replacement)	The extracellular polymeric substance matrix represents a barrier to antibiotic diffusion, shielding the inner bacteria from the antibiotic effect[56] Resistance genes are easily passed from bacteria to bacteria in the biofilm[57]	Nanoparticles that: diffuse through the extracellular matrix due to their size and reach the bacteria within inhibit bacterial efflux pumps contain heavy metals with antimicrobial effects are cationically charged, which increases interaction with the extracellular matrix	Qiu et al. recently showed that ~250nm drug-free cationic nanoparticles (CNP) were capable of time-and concentration-dependent activity against MRSA growth. These CNP were able to cause significant killing of planktonic bacteria, and completely inhibit biofilm formation[58].
Host Response	The inflammatory immune response to infection can ultimately cause damage to the host itself.	Immune response modulation requires a fine balance to promote infection clearance while minimizing inflammatory damage[59]	Combination nanoparticles that deliver antimicrobial and anti-inflammatory to the site of infection Modulation of immune amplification signaling Neutralization of inflammatory cytokines	Yang et al. co-loaded intercellular adhesion molecule-1 (I-CAM) targeted poly(lactide-co-glycolide acid) (PLGA) nanoparticles with Sparfloxacin, an antimicrobial, and Tacrolimus, an immunosuppressant drug. This combination nanoparticle preparation was able to decrease bacterial load and improve survival in a mouse pneumonia model[60].