A new nanomedicine that combines a cancer-seeking protein with a molecular “degrader” has shown targeted activity against HER2-positive tumors in cell studies and mice, offering a potential way to overcome one of the biggest obstacles facing an emerging class of anticancer drugs. The approach, developed by researchers at Shanghai Jiao Tong University, packages a proteolysis-targeting chimera, or PROTAC, into nanoparticles that are designed to recognize cancer cells, enter them and release their drug payload only after encountering the chemical environment inside the cell. In a study published in Nano Research, the team reported that the system accumulated in tumors, removed a cancer-promoting protein called BRD4 and improved antitumor effects in a mouse model of HER2-positive ovarian cancer. The work remains preclinical, but it illustrates how nanotechnology and targeted protein degradation can be combined into a single therapeutic design.
PROTACs work differently from conventional drugs that merely inhibit a protein’s activity. A typical PROTAC is a bifunctional molecule with one end that binds to a disease-associated protein and another that recruits an E3 ubiquitin ligase, part of the cell’s protein-disposal machinery. By bringing the target protein and the ligase into close proximity, the PROTAC causes the target to be tagged with ubiquitin molecules. The proteasome, a large intracellular complex that degrades ubiquitinated proteins, then dismantles the marked protein. Because a PROTAC can act catalytically—detaching after the target is destroyed and potentially engaging another copy—it may eliminate proteins rather than temporarily blocking them. That promise has attracted intense interest in oncology, where many disease-driving proteins have proved difficult to inhibit with traditional small molecules.
The same molecular features that make PROTACs powerful can also make them difficult to deliver. Many are relatively large and chemically complex, occupying what medicinal chemists call “beyond rule-of-five” space. Their size and polarity can reduce passive diffusion through the lipid bilayer of a cell membrane, while their hydrophobicity can limit water solubility and cause unfavorable distribution in the body. A PROTAC circulating in the bloodstream must reach a tumor, cross or enter cancer cells, escape destructive clearance pathways and arrive in the correct intracellular compartment before it can assemble the molecular interactions needed for protein degradation. Poor membrane permeability and inadequate tumor distribution therefore represent major barriers between promising laboratory chemistry and a practical medicine.
The researchers addressed these problems by attaching a hydrophobic PROTAC called MZ1 to a hydrophilic affibody known as ZHER2:342. MZ1 is designed to degrade bromodomain-containing protein 4, or BRD4, while the affibody is an engineered affinity protein that recognizes human epidermal growth factor receptor 2, commonly called HER2. Affibodies are small, engineered binding proteins derived from an alpha-helical bacterial receptor domain. Unlike full-size antibodies, they are compact and can be produced and chemically modified as defined molecules. ZHER2:342 supplies the targeting function, while MZ1 supplies the protein-degradation function. The two components were connected by a linker containing a disulfide bond, creating an amphiphilic conjugate with one water-compatible region and one water-avoiding region.
When placed in water, the conjugates spontaneously organized into nanoparticles, a process known as self-assembly. Amphiphilic molecules can form nanoscale structures because their hydrophilic and hydrophobic sections seek different environments: the water-compatible affibody portions remain exposed to the surrounding liquid, while the hydrophobic MZ1 portions cluster away from it. This arrangement allows the drug molecules to be carried in a compact, water-dispersible form without requiring a separate polymeric carrier or lipid shell. The resulting formulation, called the ZHER2:342-MZ1 affibody-PROTAC conjugate nanomedicine, was intended to solve two delivery problems at once—keeping MZ1 dispersed in the bloodstream and displaying the HER2-binding affibody on the nanoparticle surface.
The targeting mechanism depends on the abundance of HER2 on the surface of selected cancer cells. HER2 is a receptor tyrosine kinase involved in signaling pathways that regulate proliferation, survival and differentiation. In some breast, ovarian and other cancers, the receptor is produced at unusually high levels, creating a molecular marker that can distinguish malignant cells from many normal tissues. According to the study, the nanoparticles used HER2 receptor-mediated endocytosis to gain entry into cancer cells. In this process, binding at the cell surface triggers the membrane to fold inward and form an intracellular vesicle containing the bound material. The researchers reported effective accumulation and internalization of the conjugate in HER2-positive cancer cells in vitro, consistent with the idea that affibody-mediated recognition improved delivery beyond what free MZ1 could achieve.
The disulfide linker was designed to respond to the reducing conditions inside cells. Glutathione, or GSH, is a major intracellular antioxidant and is generally present at higher concentrations within cells than in the extracellular space or bloodstream. Its thiol group can participate in reduction reactions that cleave disulfide bonds. In the proposed system, intracellular GSH breaks the linker connecting the affibody and MZ1, releasing the PROTAC after the nanoparticle has been internalized. This is a form of chemically triggered release: the carrier remains comparatively stable during circulation but becomes labile in a cellular environment rich in reducing agents. Once liberated, MZ1 can interact with BRD4 and recruit the ubiquitin-proteasome system, converting the delivery event into targeted destruction of an intracellular protein.
BRD4 belongs to the bromodomain and extraterminal, or BET, family of epigenetic reader proteins. Rather than acting as a conventional DNA-binding transcription factor, BRD4 recognizes acetylated lysine residues on histones and other proteins, helping organize transcriptional machinery at active genes. It is particularly associated with regulatory regions such as enhancers and super-enhancers, where it can support expression programs that sustain cancer-cell proliferation and survival. Degrading BRD4 can therefore disrupt multiple transcriptional networks at once. The study reported that the released MZ1 produced BRD4 deficiency and subsequently induced apoptosis, the regulated form of cell death. This mechanism is distinct from simply slowing an enzyme: it removes an entire protein platform that cancer cells may depend on for maintaining gene expression.
The researchers then evaluated the conjugate in vivo after administration through the tail vein in mice carrying HER2-positive SKOV-3 tumors. Intravenous delivery places the formulation directly into the circulation, where its size, surface properties and targeting ligand influence how long it remains in the blood and where it accumulates. The study reported outstanding tumor-specific targeting, increased drug accumulation, enhanced BRD4 degradation and improved antitumor efficacy compared with relevant controls. These findings suggest that the nanoparticles retained their targeting function in the complex environment of an animal and that sufficient MZ1 reached tumor cells to engage its intracellular mechanism. The results also support the value of combining receptor-mediated uptake with a redox-sensitive release step, rather than relying solely on passive nanoparticle accumulation in tumors.
The work does not yet establish whether the platform is safe or effective in people. Mouse tumors do not reproduce the full biological diversity of human cancers, and HER2 expression can vary between tumors and even between cells within the same tumor. The distribution, metabolism and elimination of affibody-based nanoparticles will also need to be characterized in detail, as will possible immune responses, off-target BRD4 degradation and toxicity in healthy tissues. In addition, a clinical formulation would have to meet demanding requirements for manufacturing consistency, stability and dose control. Even so, the study points toward a versatile strategy: a compact targeting protein, a cleavable chemical linker and a self-assembling PROTAC payload are integrated into one molecule that builds its own nanomedicine. If the design can be optimized and validated in more advanced models, it could help turn targeted protein degradation from a promising intracellular concept into a more precise way of delivering cancer therapy.
Subject of Research: HER2-targeted PROTAC nanomedicine for BRD4 degradation and cancer therapy
Subject of Research: Technology and Engineering
Article Title: A self-assembled affibody-PROTAC conjugate nanomedicine for targeted cancer therapy
Article References: Li, Q., Yang, X., Zhao, M., Xia, X., Gao, W., Huang, W., Xia, X., & Yan, D. (2024). A self-assembled affibody-PROTAC conjugate nanomedicine for targeted cancer therapy. Nano Research, 17(11), 9954-9964. https://doi.org/10.1007/s12274-024-6974-x
Image Credits: AI Generated
DOI: 10.1007/s12274-024-6974-x
Keywords: affibody-PROTAC conjugate, BRD4 degradation, HER2 targeting, self-assembled nanoparticles, nanomedicine, targeted cancer therapy, proteolysis-targeting chimeras
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Rowan B. (August 29, 2026). Self-Assembled Affibody-PROTAC Nanomedicine Targets Cancer Cells. Scienmag. https://scienmag.com/self-assembled-affibody-protac-nanomedicine-targets-cancer-cells/
Rowan B. “Self-Assembled Affibody-PROTAC Nanomedicine Targets Cancer Cells.” Scienmag, 29 August 2026, https://scienmag.com/self-assembled-affibody-protac-nanomedicine-targets-cancer-cells/. Accessed 29 August 2026.
Rowan B. “Self-Assembled Affibody-PROTAC Nanomedicine Targets Cancer Cells.” Scienmag. August 29, 2026. https://scienmag.com/self-assembled-affibody-protac-nanomedicine-targets-cancer-cells/
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Tags: BRD4 protein removalBRD4 protein removal in cancerCancer-targeting nanomedicineE3 ubiquitin ligase recruitmentHER2-positive tumor therapymolecular degraders for cancer treatmentmolecular degraders in cancer treatmentnanoparticle drug delivery systemsnanoparticle-mediated targeted protein degradationnanoscale cancer therapeuticsnanotechnology in oncologyovarian cancer nanomedicineovarian cancer nanotherapypreclinical cancer nanotechnologypreclinical cancer nanotherapeuticsPROTAC-based drug deliveryPROTAC-based protein degradationself-assembled affibody-PROTAC nanomedicinetargeted cancer cell recognitiontargeted proteolysis in cancer therapytumor-specific drug release systemstumor-specific nanomedicine development
