Supramolecular self-assembly offers promising new ways to control nanostructure morphology and respond to external stimuli. A pH-sensitive self-assembled system was developed to both control nanostructure shape and respond to the acidic microenvironment of tumors using self-assembling peptide amphiphiles (PAs). By incorporating an oligo-histidine H6 sequence, we developed two PAs that self-assembled into distinct morphologies on the nanoscale, either as nanofibers or spherical micelles, based on the incorporation of the aliphatic tail on the N-terminus or near the C-terminus, respectively. Both cylinder and sphere-forming PAs demonstrated reversible disassembly between pH 6.0 and 6.5 upon protonation of the histidine residues in acidic solutions. These PAs were then characterized and assessed for their potential to encapsulate hydrophobic chemotherapies. The H6-based nanofiber assemblies encapsulated camptothecin (CPT) with up to 60% efficiency, a 7-fold increase in CPT encapsulation relative to spherical micelles. Additionally, pH-sensitive nanofibers showed improved tumor accumulation over both spherical micelles and nanofibers that did not change morphologies in acidic environments. We have demonstrated that the morphological transitions upon changes in pH of supramolecular nanostructures affect drug encapsulation and tumor accumulation. Our findings also suggest that these supramolecular events can be tuned by molecular design to improve the pharmacologic properties of nanomedicines.

Micro and nanocarriers Micro and nanoscale technologies Oral drug delivery Tissue models Oral administration is a pillar of the pharmaceutical industry and yet it remains challenging to administer hydrophilic therapeutics by the oral route. Smart and controlled oral drug delivery could bypass the physiological barriers that limit the oral delivery of these therapeutics. Micro-and nanoscale technologies, with an unprecedented ability to create, control, and measure micro-or nanoenvironments, have found tremendous applications in biology and medicine. In particular, significant advances have been made in using these technologies for oral drug delivery. In this review, we briefly describe biological barriers to oral drug delivery and micro and nanoscale fabrication technologies. Micro and nanoscale drug carriers fabricated using these technologies, including bioadhesives, microparticles, micropatches, and nanoparticles, are described. Other applications of micro and nanoscale technologies are discussed, including fabrication of devices and tissue engineering models to precisely control or assess oral drug delivery in vivo and in vitro, respectively. Strategies to advance translation of micro and nanotechnologies into clinical trials for oral drug delivery are mentioned. Finally, challenges and future prospects on further integration of micro and nanoscale technologies with oral drug delivery systems are highlighted.

Micro and nanoscale drug carriers must navigate through a plethora of dynamic biological systems prior to reaching their tissue or disease targets. The biological obstacles to drug delivery come in many forms and include tissue barriers, mucus and bacterial biofilm hydrogels, the immune system, and cellular uptake and intracellular trafficking. The biointerface of drug carriers influences how these carriers navigate and overcome biological barriers for successful drug delivery. In this review, we examine how key material design parameters lead to dynamic biointerfaces and improved drug delivery across biological barriers. We provide a brief overview of approaches used to engineer key physicochemical properties of drug carriers, such as morphology, surface chemistry, and topography, as well as the development of dynamic responsive materials for barrier navigation. We then discuss essential biological barriers and how biointerface engineering can enable drug carriers to better navigate and overcome these barriers to drug delivery.

Glioblastoma is a particularly challenging cancer, as there are currently limited options for treatment. New delivery routes are being explored, including direct intratumoral injection via convection-enhanced delivery (CED). While promising, convection-enhanced delivery of traditional chemotherapeutics such as doxorubicin (DOX) has seen limited success. Several studies have demonstrated that attaching a drug to polymeric nanoscale materials can improve drug delivery efficacy via CED. We therefore set out to evaluate a panel of morphologically distinct protein nanoparticles for their potential as CED drug delivery vehicles for glioblastoma treatment. The panel consisted of three different virus-like particles (VLPs), MS2 spheres, tobacco mosaic virus (TMV) disks and nanophage filamentous rods modified with DOX. While all three VLPs displayed adequate drug delivery and cell uptake in vitro, increased survival rates were only observed for glioma-bearing mice that were treated via CED with TMV disks and MS2 spheres conjugated to doxorubicin, with TMV-treated mice showing the best response. Importantly, these improved survival rates were observed after only a single VLP–DOX CED injection several orders of magnitude smaller than traditional IV doses. Overall, this study underscores the potential of nanoscale chemotherapeutic CED using virus-like particles and illustrates the need for further studies into how the overall morphology of VLPs influences their drug delivery properties.

Current approaches to nanoscale therapeutic delivery rely on the attachment of a drug of interest to a nanomaterial scaffold that is capable of releasing the drug selectively in a tumor environment. One class of nanocarriers receiving significant attention is protein nanomaterials, which are biodegradable and homogeneous in morphology and can be equipped with multiple functional handles for drug attachment. Although most protein-based nanocarriers are spherical in morphology, recent research has revealed that nonspherical nanomaterials may have favorable tumor uptake in comparison to their spherical counterparts. It is therefore important to expand the number of nonspherical protein-based nanocarriers that are available. Herein, we report the development of a self-assembling nanoscale disk derived from a double arginine mutant of recombinantly expressed tobacco mosaic virus coat protein (RR-TMV). RR-TMV disks display highly stable double-disk assembly states. These RR-TMV disks were functionalized with the chemotherapy drug doxorubicin (DOX) and further modified with polyethylene glycol (PEG) for improved solubility. RR-TMV displayed cytotoxic properties similar to those of DOX alone when incubated with U87MG glioblastoma cells, but unmodified RR-TMV did not cause any cytotoxicity. The RR-TMV disk assembly represents a promising protein-based nanomaterial for applications in drug delivery.