Lung cancers, malignant mesotheliomas (MM), and fibrosis are devastating diseases with limited treatment strategies, in part due to poorly effective drug delivery to affected areas of lung. We hypothesized that acid prepared mesoporous spheres (APMS) (1-2 µm diameter, 40Angstrom pore size), might be effective vehicles for pulmonary chemotherapeutic drug delivery. To assess this, APMS, chemically modified with different surface molecules [lipid, a linker having a terminal amine group, a thiol group, or tetraethylene glycol (TEG)], were evaluated for uptake and possible cytotoxic effects following in vitro administration to murine alveolar epithelial Type II (C10) and human mesothelioma (MM) cells and after intrapleural (IP) or intranasal (IN) administration to C57/BL6 mice. APMS coated with TEG (APMS-TEG) were most efficiently taken up by C10 and MM cells. The mechanism of cell uptake was rapid, actin-dependent, and did not involve clathrin or caveolae-mediated mechanisms nor fusion of membrane-bound APMS with lysosomes. When injected IP in mice, APMS-TEG were taken up by both CD45-positive and -negative cells of the diaphragm, lung and spleen whereas APMS administered by the IN route were predominantly in lung epithelial cells and alveolar macrophages. After IP or IN administration, APMS were non-immunogenic and non-toxic as evaluated by differential cell counts and lactate dehydrogenase (LDH) levels in bronchoalveolar and pleural lavage fluids (BALF, PLF). In the treatment of lung and pleural diseases, APMS-TEG may be useful tools to deliver chemotherapeutic drugs or molecular constructs.