Table 1: Summary discussion of all the advantages and caveats for each of the design features and solution summarily presented in Figure 1.

Size

Very small particles are quickly cleared through renal filtration and in cone cases can penetrate the nuclei causing high toxicity.
Very large nanoparticles are not suitable for IV injection: their aggregation can induce capillaries clogging and embolism.
20–200 nm nanoparticles are considered the range to achieve EPR-mediated NPs passive targeting.
Smaller particles more easily penetrate tissues parenchyma and display better mucoadhesion.
Larger particles injected locally are more efficiently retained in the tissue, because they diffuse less.
Some NPs have size-dependent physiochemical proprieties (e.g., fluorescence for quantum dots, SPR for gold NPs, and superparamagnetism for SPIONs).

Shape

Spherical particles are the most widely diffused shape because they provide minimal surface-to-volume ratio, minimizing the energy state in self-assembling formulations.
For nonspherical particles, the hydrodynamic diameter more closely resembles the diameter of the smallest dimension, thus influencing biodistribution.
Nonspherical NPs interact more efficiently with cells and mucosae along their largest dimension.
Some NPs have shape-dependent intrinsic physiochemical proprieties (e.g., SPR for gold nanoconstructs and optical proprieties for carbon NPs).

Surface features

ChargeHighly positive NPs strongly interact with negatively charged cell membranes and enhance uptake. However, they are not suitable for systemic administration because they also interact with proteins and cells in blood, becoming quickly opsonized and cleared by RES, or aggregation and potential embolism.
Highly positive NPs interact strongly with the extracellular matrix when injected locally, and with mucosae.
Highly negative NPs are similarly quickly cleared by RES.
RoughnessNPs with a rough surface have higher surface and interact more with proteins when administered IV.
Active targeting moietiesInclude: small molecules (e.g., mannose, folic acid, and synthetic oligopeptides), proteins (antibodies and antibody fragments, toxins binding sites, and receptor ligands such as transferrin and albumin), aptamers, and adhesion/housing molecules for biomimetic platforms.
Allow for better tissue targeting, complementing passive targeting strategies.
Stealth-inducing moleculesInclude a wide range of neutrally charged, highly hydrophilic natural and synthetic polymers (e.g., PEG, PEI, polyglycerols, hydrophilic polyacrylates, chitosan, and dextran) and “self’ molecules for personalized biomimetic formulations.
Increase the plasmatic half-life of administered NPs by slowing opsonisation, allowing more accumulation in the target tissue.
Label/drug binding scaffoldsProvide binding moieties for both drugs, photosensitizers, and imaging molecules.

Material

Carbon NPsHave specific optical proprieties.
High potential for systemic toxicity.
LiposomesAre widely studied and can load both hydrophilic and lipophilic molecules, including proteins.
Are well tolerated and some liposomal formulations are already FDA-approved.
Solid lipid NPsProvide high loading for lipophilic drugs and can modulate their release.
Biodegradable.
DendrimersGood size control and multiplexing capabilities.
Polymeric NPsWide range of materials and material blends to accommodate many different molecules and functions (e.g., pH dependence, and biodegradability).
Gold NPsChemically inert, provide X-ray and radiotherapy enhancement, tunable SPR, Sonodynamic and photodynamic therapies, and SERS.
Superparamagnetic iron oxide NPsProvide high contrast for MRI imaging, magnetic field-guided tissue accumulation, and magnetic hyperthermia.
Biodegradable and well tolerated.
Quantum dotsHigh fluorescence yield and photostability.
Concerns about systemic toxicity.