Size and charge are essential designing factors for cartilage targeting, thus a panel of four NPs was designed to model both surface binding and cartilage uptake drug delivery strategies (Figure ). Cartilage ECM is porous and allows the diffusion of small NPs (≤ 15 nm) thus dendrimeric PAMAM NPs (NP0, NP5000) were synthesized to enable the penetration of the full thickness of cartilage tissue. One of the PAMAM dendrimers was PEGylated (NP5000), yielding two types of small, cationic NPs with similar sizes yet distinct zeta potentials (NP0 = 6.0 nm, +16.5 mV; NP5000 = 8.6 nm, +6.4 mV). Additionally, PLGA-based NPs, with larger diameters were generated to model drug delivery carriers that target the cartilage surface. These NPs had a size that prevented them from penetrating the tissue. Cationic profiles of the PLGA NPs were achieved by surface modifications using a blend of PEG and PEI (Figure , Supporting Information) with varied ratios, yielding PLGA-PEIH (270.3 nm, +22.2 mV) and PLGA-PEIL (265.2 nm, +3.8 mV) NPs. Resazurin viability assay was used to evaluate the cytotoxic effects of both the PAMAM NPs, as described previously , and the PLGA NPs utilizing U937 monocytes (Figure , Supporting Information) demonstrating that they are non-toxic at the used concentrations.