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1. Peptide-Based Vectors: A Biomolecular Engineering Strategy for Gene Delivery

   https://doi.org/10.1146/annurev-chembioeng-101121-070232  

   Urandur, Sandeep; Sullivan, Millicent O (June 2023, Annual Review of Chemical and Biomolecular Engineering)

   From the first clinical trial by Dr. W.F. Anderson to the most recent US Food and Drug Administration–approved Luxturna (Spark Therapeutics, 2017) and Zolgensma (Novartis, 2019), gene therapy has revamped thinking and practice around cancer treatment and improved survival rates for adult and pediatric patients with genetic diseases. A major challenge to advancing gene therapies for a broader array of applications lies in safely delivering nucleic acids to their intended sites of action. Peptides offer unique potential to improve nucleic acid delivery based on their versatile and tunable interactions with biomolecules and cells. Cell-penetrating peptides and intracellular targeting peptides have received particular focus due to their promise for improving the delivery of gene therapies into cells. We highlight key examples of peptide-assisted, targeted gene delivery to cancer-specific signatures involved in tumor growth and subcellular organelle–targeting peptides, as well as emerging strategies to enhance peptide stability and bioavailability that will support long-term implementation. 

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2. Mitochondrial Targeting Peptide-based Nanodelivery for Cancer Treatment

   https://doi.org/10.2174/1389203723666220520160435  

   Ehsan, Sumia; Covarrubias-Zambrano, Obdulia; Bossmann, Stefan H. (October 2022, Current Protein & Peptide Science)

   Abstract: Mitochondria are important intracellular organelles because of their key roles in cellular metabolism,proliferation, and programmed cell death. The differences in the structure and function of themitochondria of healthy and cancerous cells have made mitochondria an interesting target for drug delivery.Mitochondrial targeting is an emerging field as the targeted delivery of cytotoxic payloads andantioxidants to the mitochondrial DNA is capable of overcoming multidrug resistance. Mitochondrialtargeting is preferred over nuclear targeting because it can take advantage of the distorted metabolismin cancer. The negative membrane potential of the inner and outer mitochondrial membranes, as well astheir lipophilicity, are known to be the features that drive the entry of compatible targeting moiety,along with anticancer drug conjugates, towards mitochondria. The design of such drug nanocarrier conjugatesis challenging because they need not only to target the specific tumor/cancer site but have toovercome multiple barriers as well, such as the cell membrane and mitochondrial membrane. This reviewfocuses on the use of peptide-based nanocarriers (organic nanostructures such as liposomes, inorganic,carbon-based, and polymers) for mitochondrial targeting of the tumor/cancer. Both invitro and in vivo key results are reported. 

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3. Iterative Design Reveals Molecular Domain Relationships in Supramolecular Peptide–Drug Conjugates

   https://doi.org/10.1021/acs.biomac.4c00519  

   Sis, Matthew J; Liu, Dongping; Allen, Isabella; Webber, Matthew J (July 2024, Biomacromolecules)

   Supramolecular peptide-drug conjugates (sPDCs) are prepared by covalent attachment of a drug moiety to a peptide motif programmed for one-dimensional self-assembly, with subsequent physical entanglement of these fibrillar structures enabling formation of nanofibrous hydrogels. This class of prodrug materials presents an attractive platform for mass-efficient and site-specific delivery of therapeutic agents using a discrete single-component molecular design. However, a continued challenge in sPDC development is elucidating relationships between supramolecular interactions in their drug and peptide domains and the resultant impact of these domains on assembly outcomes and material properties. Inclusion of a saturated alkyl segment alongside the prodrug in the hydrophobic domain of sPDCs could relieve some of the necessity for ordered, prodrug-produg interactions. Accordingly, nine sPDCs are prepared here to iterate the design variables of amino acid sequence and hydrophobic prodrug/alkyl block design. All molecules spontaneously formed hydrogels under physiological conditions, indicating a less hindered thermodynamic path to self-assembly relative to previous prodrug-only designs. However, material studies on the supramolecular arrangement, formation, and mechanical properties of the resultant sPDC hydrogels, as well as their drug release profiles, showed complex relationships between the hydrophobic and peptide domains in the formation and function of the resulting assemblies. Together, these results indicate that sPDC material properties are intrinsically linked to holistic molecular design, with coupled contributions from their prodrug and peptide domains in directing properties of the emergent materials. 

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4. Engineered protein–iron oxide hybrid biomaterial for MRI-traceable drug encapsulation

   https://doi.org/10.1039/d2me00002d  

   Hill, Lindsay K.; Britton, Dustin; Jihad, Teeba; Punia, Kamia; Xie, Xuan; Delgado-Fukushima, Erika; Liu, Che Fu; Mishkit, Orin; Liu, Chengliang; Hu, Chunhua; et al (August 2022, Molecular Systems Design & Engineering)

   Labeled protein-based biomaterials have become popular for various biomedical applications such as tissue-engineered, therapeutic, and diagnostic scaffolds. Labeling of protein biomaterials, including with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, has enabled a wide variety of imaging and therapeutic techniques. These USPIO-based biomaterials are widely studied in magnetic resonance imaging (MRI), thermotherapy, and magnetically-driven drug delivery, which provide a method for direct and non-invasive monitoring of implants or drug delivery agents. Where most developments have been made using polymers or collagen hydrogels, shown here is the use of a rationally designed protein as the building block for a meso-scale fiber. While USPIOs have been chemically conjugated to antibodies, glycoproteins, and tissue-engineered scaffolds for targeting or improved biocompatibility and stability, these constructs have predominantly served as diagnostic agents and often involve harsh conditions for USPIO synthesis. Here, we present an engineered protein–iron oxide hybrid material comprised of an azide-functionalized coiled-coil protein with small molecule binding capacity conjugated via bioorthogonal azide–alkyne cycloaddition to an alkyne-bearing iron oxide templating peptide, CMms6, for USPIO biomineralization under mild conditions. The coiled-coil protein, dubbed Q, has been previously shown to form nanofibers and, upon small molecule binding, further assembles into mesofibers via encapsulation and aggregation. The resulting hybrid material is capable of doxorubicin encapsulation as well as sensitive -weighted MRI darkening for strong imaging capability that is uniquely derived from a coiled-coil protein. 

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5. Fluorinated peptide biomaterials

   https://doi.org/10.1002/pep2.24184  

   Sloand, Janna N.; Miller, Michael A.; Medina, Scott H. (July 2020, Peptide Science)

   Abstract Fluorinated compounds, while rarely used by nature, are emerging as fundamental ingredients in biomedical research, with applications in drug discovery, metabolomics, biospectroscopy, and, as the focus of this review, peptide/protein engineering. Leveraging the fluorous effect to direct peptide assembly has evolved an entirely new class of organofluorine building blocks from which unique and bioactive materials can be constructed. Here, we discuss three distinct peptide fluorination strategies used to design and induce peptide assembly into nano‐, micro‐, and macro‐supramolecular states that potentiate high‐ordered organization into material scaffolds. These fluorine‐tailored peptide assemblies employ the unique fluorous environment to boost biofunctionality for a broad range of applications, from drug delivery to antibacterial coatings. This review provides foundational tactics for peptide fluorination and discusses the utility of these fluorous‐directed hierarchical structures as material platforms in diverse biomedical applications. 

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