NP1 and NP1-MNP rapidly stimulate phosphorylation of ERK1/2 (pERK1/2). (A) MC3T3-E1 cells were serum starved overnight and treated with NP1 for the indicated time (minutes). Anisomycin (ani) (2.5 μg/mL, 30 min) was used as a positive control for p38 and pJNK. Cells were harvested and analyzed by Western blotting. (B) MC3T3-E1 cells were pretreated with inhibitors for ERK1/2 (U0126–30 μM), JNK (SP600125–10 μM), and p38 (SB203580–10 μM) followed by treatment with NP1 for 15 min and analyzed by Western blotting. (C) MC3T3-E1 cells were pretreated with the caveolae/lipid raft inhibitor MβCD for 2 h followed by addition of NP1-MNP (100 μg/mL) for 15 min, and the resulting samples were analyzed by Western blotting. (D) MC3T3-E1 cells were pretreated with U0126 (30 μM) or control followed by addition of NP1 for 45 min, and the resulting samples were analyzed for the conversation of LC3β-I to LC3β-II, p62, and actin by Western blotting. (E) MC3T3-E1 cells were pretreated with U0126 (30 μM) or control followed by NP1 (60 μg/mL) for 20 h, and fluorescent and light microscopy were used for detection of nanoparticle internalization.