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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. Primary Human Breast Cancer‐Associated Endothelial Cells Favor Interactions with Nanomedicines

   https://doi.org/10.1002/adma.202403986  

   Wang, Lin; Sheth, Vinit; Liu, Kaili; Panja, Prasanta; Frickenstein, Alex N; He, Yuxin; Yang, Wen; Thomas, Abigail G; Jamei, Mohammad Hasan; Park, Jeesoo; et al (May 2024, Advanced Materials)

   Abstract Cancer nanomedicines predominately rely on transport processes controlled by tumor‐associated endothelial cells to deliver therapeutic and diagnostic payloads into solid tumors. While the dominant role of this class of endothelial cells for nanoparticle transport and tumor delivery is established in animal models, the translational potential in human cells needs exploration. Using primary human breast cancer as a model, the differential interactions of normal and tumor‐associated endothelial cells with clinically relevant nanomedicine formulations are explored and quantified. Primary human breast cancer‐associated endothelial cells exhibit up to ≈2 times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. Super‐resolution imaging studies reveal a significantly higher intracellular vesicle number for tumor‐associated endothelial cells, indicating a substantial increase in cellular transport activities. RNA sequencing and gene expression analysis indicate the upregulation of transport‐related genes, especially motor protein genes, in tumor‐associated endothelial cells. Collectively, the results demonstrate that primary human breast cancer‐associated endothelial cells exhibit enhanced interactions with nanomedicines, suggesting a potentially significant role for these cells in nanoparticle tumor delivery in human patients. Engineering nanoparticles that leverage the translational potential of tumor‐associated endothelial cell‐mediated transport into human solid tumors may lead to the development of safer and more effective clinical cancer nanomedicines. 

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3. DNA-Templated Spatially Controlled Proteolysis Targeting Chimera for Cyclin D1–CDK4/6 Complex Protein Degradation

   https://doi.org/10.1021/jacs.5c04918  

   Zheng, Rong; Prasad, Abhay; Satyabola, Deeksha; Xu, Yang; Roy, Subhajit; Yan, Yichen; Šulc, Petr; Yan, Hao (August 2025, Journal of the American Chemical Society)

   Constraining proximity-based drugs, such as proteolysis targeting chimeras (PROTACs), into their bioactive conformation can significantly impact their selectivity and potency. However, traditional methods for achieving this often involve complex and time-consuming synthetic procedures. Here, we introduced an alternative approach by demonstrating DNA-templated spatially controlled PROTACs (DTACs), which leverage the programmability of nucleic acid-based self-assembly for efficient synthesis and offer precise control over inhibitors’ spacing and orientation. The resulting constructs revealed distance- and orientation-dependent selectivity and degradation potency for the Cyclin D1–CDK4/6 protein complex in cancer cells. Notably, the optimal construct DTAC-V1 demonstrated unprecedented synchronous degradation of the entire Cyclin D1–CDK4/6 complex, leading to robust G1-phase cell cycle arrest and effective inhibition of cancer cell proliferation. Furthermore, in a xenograft mouse model, DTAC-V1 exhibited potent therapeutic efficacy by effectively degrading Cyclin D1–CDK4/6 and suppressing tumor growth, underscoring its potential as an anticancer agent. Overall, our findings demonstrate the feasibility of DTAC as a rapid, scalable, and modular platform for the spatial control of functional inhibitors for optimal effectiveness, making it a promising method for proximity-based therapeutics. 

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4. Nanomaterials for Protein Delivery in Anticancer Applications

   https://doi.org/10.3390/pharmaceutics13020155  

   Yau, Anne; Lee, Jinhyung; Chen, Yupeng (February 2021, Pharmaceutics)

   null (Ed.)

   Nanotechnology platforms, such as nanoparticles, liposomes, dendrimers, and micelles have been studied extensively for various drug deliveries, to treat or prevent diseases by modulating physiological or pathological processes. The delivery drug molecules range from traditional small molecules to recently developed biologics, such as proteins, peptides, and nucleic acids. Among them, proteins have shown a series of advantages and potential in various therapeutic applications, such as introducing therapeutic proteins due to genetic defects, or used as nanocarriers for anticancer agents to decelerate tumor growth or control metastasis. This review discusses the existing nanoparticle delivery systems, introducing design strategies, advantages of using each system, and possible limitations. Moreover, we will examine the intracellular delivery of different protein therapeutics, such as antibodies, antigens, and gene editing proteins into the host cells to achieve anticancer effects and cancer vaccines. Finally, we explore the current applications of protein delivery in anticancer treatments. 

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5. Leveraging intracellular ALDH1A1 activity for selective cancer stem-like cell labeling and targeted treatment via in vivo click reaction

   https://doi.org/10.1073/pnas.2302342120  

   Bo, Yang; Zhou, Jingyi; Cai, Kaimin; Wang, Ying; Feng, Yujun; Li, Wenming; Jiang, Yunjiang; Kuo, Shanny Hsuan; Roy, Jarron; Anorma, Chelsea; et al (September 2023, Proceedings of the National Academy of Sciences)

   Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are “nonlethal,” in that the inhibition of the enzymes’ activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm³). 

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