Nanoparticle interacts with live cells depending on their surface chemistry, enters into cell via endocytosis, and is commonly trafficked to an endosome/lysozome that restricts subcellular targeting options. Here we show that nanoparticle surface chemistry can be tuned to alter their cell uptake mechanism and subcellular trafficking. Quantum dot based nanoprobes of 20-30 nm hydrodynamic diameters have been synthesized with tunable surface charge (between +15 mV to -25 mV) and lipophilicity to influence their cellular uptake processes and subcellular trafficking. It is observed that cationic nanoprobe electrostatically interacts with cell membrane and enters into cell via clathrin-mediated endocytosis. At lower surface charge (between +10 mV to -10 mV), the electrostatic interaction with cell membrane becomes weaker, and additional lipid raft endocytosis is initiated. If a lipophilic functional group is introduced on a weakly anionic nanoparticle surface, the uptake mechanism shifts to predominant lipid raft-mediated endocytosis. In particular, the zwitterionic-lipophilic nanoprobe has the unique advantage as it weakly interacts with anionic cell membrane, migrates toward lipid rafts for interaction through lipophilic functional group, and induces lipid raft-mediated endocytosis. While predominate or partial clathrin-mediated entry traffics most of the nanoprobes to lysozome, predominate lipid raft-mediated entry traffics them to perinuclear region, particularly to the Golgi apparatus. This finding would guide in designing appropriate nanoprobe for subcellular targeting and delivery.

Although various nanoparticle based cellular imaging probes are reported as alternatives for conventional molecular probes, the development of nanoparticle based subcellular imaging probes is challenging. Here we report inorganic nanoparticle based fluorescent probes of 30−40 nm hydrodynamic diameter that can target and label mitochondia. Nanoprobe has pH responsive polyacrylate shell with both anionic and cationic surface charge and functionalized with triphenylphosphonium group. Optimized surface chemistry offers high cellular uptake via predominate caveolae mediated endocytosis, and triphenylphosphonium group traffics them to mitochondria. This concept of surface chemistry can be extended to different nanoparticles and for development of other subcellular imaging nanoprobes.

Chemically and biochemically functionalized colloidal nanoparticles with appropriate surface chemistry are essential for various biomedical applications. Although a variety of approaches are now available in making such functional nanoparticles and nanobioconjugates, the lack of complementary surface chemistry often leads to poor performance with respect to intended biomedical applications. This feature article will focus on our efforts to make colloidal nanobioconjugates with appropriate/complementary surface chemistry for better performance of a designed nanoprobe with respect to cellular and subcellular targeting applications. In particular, we emphasize polyacrylate-based coating chemistry followed by a conjugation strategy for transforming <10 nm inorganic nanoparticle to colloidal nanoprobe of 20-50 nm hydrodynamic size. We show that a colloidal nanoprobe can be chemically designed to control the cell-nanoparticle interaction, cellular endocytosis, and targeting/labeling of subcellular compartments. Further study should be directed to adapt this surface chemistry to different nanoparticles, fine tune the surface chemistry for targeting/imaging on the subcellular/molecular length scale, and develop a delivery nanocarrier for subcellular compartments.

Although graphene based drug delivery has gained significant recent interest, the synthesis of colloidal graphene based nanocarriers with high drug loading capacities and with targeting ligands at the outer surface is a challenging issue. We have synthesized carbohydrate coated and folate functionalized colloidal graphene which can be used as a nanocarrier for a wide variety of hydrophobic and hydrophilic drugs. The synthesized colloidal graphene is loaded with paclitaxol, camptothecin, doxorubicin, curcumin and used for their targeted delivery to cancer cells. We demonstrate that this drug loaded functional graphene nanocarrier can successfully deliver drugs into target cells and offers an enhanced therapeutic performance. The reported approach can be extended to the cellular delivery of other hydrophobic and hydrophilic drugs and the simultaneous delivery of multiple drugs.

Although the antioxidant property of vitamin C is well-known for protecting cells from oxidative stress, a recent study shows that it can also generate oxidative stress under a high intracellular concentration and induce cell death. However, poor chemical stability and low biological concentration (micromolar) of vitamin C restrict its function primarily as an antioxidant. Here, we report two different nanoparticle forms of vitamin C with its intact chemical stability, glucose-responsive release from nanoparticle, and efficient cell delivery in micro to millimolar concentrations. Nanoparticles are composed of silica-coated Au nanoparticles or lipophilic polyaspartic acid-based polymer micelles which are conjugated with vitamin C via phenylboronic acid. Surface chemistry of nanoparticles is optimized for an efficient cellular interaction/uptake and for cell delivery of vitamin C. We found that vitamin C protects cells from oxidative stress at micromolar concentrations, but at millimolar concentrations, it induces cell death by generating oxidative stress. In particular, high-dose vitamin C produces HO, disrupts the cellular redox balance, and induces cell death. This study highlights the concentration-dependent biological performance of vitamin C and the requirement of a high-dose cell delivery approach for enhanced therapeutic benefit.