Effective drug delivery to pulmonary sites will benefit from the design and synthesis of novel drug delivery systems that can overcome various tissue and cellular barriers. Cell penetrating peptides (CPPs) have shown promise for intracellular delivery of various imaging probes and therapeutics. Although CPPs improve delivery efficacy to a certain extent, they still lack the scope of engineering to improve the payload capacity and protect the payload from the physiological environment in drug delivery applications. Inspired by recent advances of CPPs and CPPfunctionalized nanoparticles, in this work, we demonstrate a novel nanocomposite consisting of fiber-forming supramolecular CPPs that are coated onto polylactic-glycolic acid (PLGA) nanoparticles to enhance pulmonary drug delivery. These nanocomposites show a threefold higher intracellular delivery of nanoparticles in various cells including primary lung epithelial cells, macrophages, and a 10-fold increase in endothelial cells compared to naked PLGA nanoparticles or a twofold increase compared to nanoparticles modified with traditional monomeric CPPs. Cell uptake studies suggest that nanocomposites likely enter cells through mixed macropinocytosis and passive energy-independent mechanisms, which is followed by endosomal escape within 24 h. Nanocomposites also showed potent mucus permeation. More importantly, freeze-drying and nebulizing formulated nanocomposite powder did not affect their physiochemical and biological activity, which further highlights the translative potential for use as a stable drug carrier for pulmonary drug delivery. We expect nanocomposites based on peptide nanofibers, and PLGA nanoparticles can be custom designed to encapsulate and deliver a wide range of therapeutics including nucleic acids, proteins, and small-molecule drugs when employed in inhalable systems to treat various pulmonary diseases.

Lung cancer is one of the major causes of cancer-related deaths worldwide, primarily because of the limitations of conventional clinical therapies such as chemotherapy and radiation therapy. Side effects associated with these treatments have made it essential for new modalities, such as tumor targeting nanoparticles that can provide cancer specific therapies. In this research, we have developed novel dual-stimuli nanoparticles (E-DSNPs), comprised of two parts; (1) Core: responsive to glutathione as stimuli and encapsulating Cisplatin (a chemo-drug), and (2) Shell: responsive to irradiation as stimuli and containing NU7441 (a radiation sensitizer). The targeting moieties on these nanoparticles are Ephrin transmembrane receptors A2 (EphA2) that are highly expressed on the surfaces of lung cancer cells. These nanoparticles were then evaluated for their enhanced targeting and therapeutic efficiency against lung cancer cell lines. E-DSNPs displayed very high uptake by lung cancer cells compared to healthy lung epithelial cells. These nanoparticles also demonstrated a triggered release of both drugs against respective stimuli and a subsequent reduction in in vitro cancer cell survival fraction compared to free drugs of equivalent concentration (survival fraction of about 0.019 and 0.19, respectively). Thus, these nanoparticles could potentially pave the path to targeted cancer therapy, while overcoming the side effects of conventional clinical therapies.