Plant Nanoparticles Deliver a Protein-Degrading Drug That Strikes Colorectal Cancer

Colorectal cancer remains one of the most lethal malignancies worldwide, with an estimated 1.9 million new cases and roughly 904,000 deaths recorded globally in 2022. For patients diagnosed at an advanced stage, the five-year survival rate falls below 15 percent, a stark reminder that current therapeutic options are inadequate. Existing targeted therapies directed at epidermal growth factor receptor and vascular endothelial growth factor are frequently undermined by resistance and by their dependence on the expression levels of those targets. Now, a research team has reported a fundamentally different approach: a synthetic molecule that does not merely inhibit a cancer-driving protein but destroys it outright, ferried into tumors by tiny vesicles harvested from a medicinal plant.

The protein at the center of the new work is the retinoic acid receptor alpha, or RARα, which is highly active in colorectal tumors and drives both proliferation and metastatic invasion. Traditional RARα modulators, built on retinoic acid scaffolds, suffer from chemical instability, excessive lipophilicity, and poor oral bioavailability, and they can provoke toxicity in the liver, skin, and bones. To escape these limitations, the researchers turned to proteolysis-targeting chimera, or PROTAC, technology. PROTACs are bifunctional molecules that simultaneously grip a target protein and an E3 ubiquitin ligase, forming a ternary complex that tags the target for destruction by the cell’s own ubiquitin–proteasome system. Because each PROTAC molecule dissociates after every degradation event and can engage targets repeatedly, this catalytic mechanism holds the promise of overcoming the drug resistance that plagues conventional inhibitors.

The team began with AR7, an atypical RARα antagonist, and selected its optimized derivative CA77.1 as the target-binding ligand. Molecular docking against the RARα structure (PDB:5K13) revealed that CA77.1 binds with a calculated energy of −7.379 kcal/mol, anchored by a key hydrogen bond to Arg276 and an extensive hydrophobic network. Crucially, a terminal methyl group on CA77.1 protrudes into the solvent-exposed region outside the ligand-binding pocket, providing an ideal attachment point for a linker without disturbing the core binding interactions. By covalently joining CA77.1 to thalidomide, a ligand for the E3 ubiquitin ligase CRBN, the researchers created a degrader that remains active in both oxygen-rich and hypoxic tumor regions, overcoming the hypoxia-dependent activation that limited the parent compounds.

Through systematic synthesis of six candidate molecules with varying carbon-chain and piperazine linkers, the team identified Z1 as the standout. Z1 degraded RARα with a DC50 of 6.02 ± 1.05 μM and a maximum degradation of 85.4 percent, an activity roughly 43.6 times greater than that of CA77.1 itself. Western blotting confirmed that Z1 left the related receptors RARβ and RARγ untouched, demonstrating high subtype selectivity. Mechanistic experiments sealed the case: cycloheximide chase assays showed accelerated decay of pre-existing RARα protein, while pre-treatment with the competitive ligand ATRA, the E1 enzyme inhibitor MLN4924, the proteasome inhibitor MG132, or excess thalidomide all blocked degradation, confirming the classical PROTAC pathway of direct binding and ubiquitin-proteasome-mediated clearance.

Molecular dynamics simulations running 100 nanoseconds provided atomistic support for the design. Z1 formed stable hydrogen bonds with both RARα and CRBN, with calculated binding free energies of −139.394 kJ/mol and −111.138 kJ/mol respectively, and per-residue energy decomposition pinpointed Pro407, Val395, and Ser225 as the thermodynamic core of RARα recognition. Functionally, Z1-induced degradation suppressed phosphorylation of AKT at Ser473 in a concentration-dependent manner while leaving total AKT unchanged, and it markedly reduced expression of MMP2, an enzyme that tumors use to invade surrounding tissue. This AKT–MMP2 axis, the authors note, had not been systematically characterized in earlier RARα degradation studies and offers a fresh mechanistic window into how acute protein elimination restrains cancer progression.

In vitro assays in HCT116 colorectal cancer cells painted a striking picture of Z1’s antitumor potency. Flow cytometry showed concentration-dependent arrest of cells at the G2/M phase, with the arrested population rising 3.7-fold at 100 μM. At 50 μM, Z1 completely abolished colony formation, whereas the same concentration of CA77.1 allowed more than 300 colonies to grow. Annexin V staining revealed that Z1 drove 34.6 to 55.2 percent of cells into late apoptosis, well above the 24.6 percent seen with CA77.1. Scratch assays demonstrated up to 90.4 percent inhibition of cell migration, and Transwell experiments showed that 50 μM Z1 cut the invasion rate to 10.8 percent, an 81.2 percent reduction relative to the parent compound.

Yet like all PROTACs, Z1 carries the field’s chronic handicaps: high molecular weight, poor water solubility, and weak membrane permeability. The team’s solution came from an unexpected source, the roots of Polygonatum sibiricum, a plant long valued in traditional medicine. Using a juicing, filtration, and ultracentrifugation workflow, the researchers isolated exosome-like nanoparticles, or PsELNs, that measure roughly 116 nanometers across, carry a mildly negative zeta potential of −5.8 mV, and display the characteristic disk-like morphology of plant vesicles. Their cargo of triglycerides forms a hydrophobic core that stabilizes hydrophobic drugs, while their natural tropism for colonic tissue and their ability to accumulate in tumors through the enhanced permeability and retention effect make them unusually well suited to colorectal cancer applications.

Encapsulation of Z1 within PsELNs achieved a drug-loading efficiency of 43.1 percent, exceeding values reported for goji berry and ginger vesicles, and the loaded particles grew only modestly to 143 nm while retaining an intact bilayer. Stability testing was impressive: at acidic pH 5.5 mimicking the tumor microenvironment, 77.38 percent of Z1 remained intact after 24 hours versus just 40.65 percent for the free drug, and the formulation resisted thermal stress at 44 °C, stayed stable in serum for 72 hours, and showed minimal leakage over 60 days of storage. Confocal microscopy and flow cytometry confirmed that Z1/PsELNs entered HCT116 cells far more efficiently than free Z1, and the encapsulated drug degraded RARα with a DC50 of 2.95 μM, a 2.2-fold improvement that translated into stronger apoptosis induction and greater cytotoxicity in vitro.

The decisive test came in living animals. Near-infrared imaging of tumor-bearing nude mice showed that DiR-labeled PsELNs accumulated in tumors at 2.13 times the level of the free dye, peaking at 24 hours after injection, while hemolysis rates below 5 percent confirmed blood compatibility. Over 16 days of tail-vein treatment, the Z1/PsELNs group showed significantly stronger tumor growth inhibition than mice receiving free Z1, with in vivo antitumor efficacy increasing 1.8-fold. Histopathology revealed extensive tumor cell damage, Ki67 staining showed the fewest proliferating cells, and both immunohistochemistry and Western blotting confirmed the lowest RARα levels in the nanoparticle-treated tumors, all without body-weight loss or organ damage. The authors propose that the intestinal stability and colon-targeting behavior of PsELNs could eventually support an oral PROTAC formulation, a goal that would address both gastrointestinal degradation and site-specific accumulation. By fusing event-driven protein degradation chemistry with a biocompatible, naturally derived delivery vehicle, the study charts a credible translational path for PROTAC therapeutics in colorectal cancer and illustrates how plant nanotechnology may help the next generation of degrader drugs reach their targets intact.

Subject of Research: A RARα-targeting PROTAC delivered by Polygonatum sibiricum exosome-like nanoparticles for colorectal cancer therapy

Article Title: Synthesis of RARα–PROTAC and its delivery via Polygonatum sibiricum exosome-like nanoparticles for the treatment of colorectal cancer

Article References: Zhu, G., Zhao, Y., Chen, M., Lu, S., Xu, L., Chen, G., Zeng, L., & Chen, J. (2026). Synthesis of RARα–PROTAC and its delivery via Polygonatum sibiricum exosome-like nanoparticles for the treatment of colorectal cancer. Materials Today Bio, 40, Article 103651. https://doi.org/10.1016/j.mtbio.2026.103651

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103651

Keywords: colorectal cancer, PROTAC, RARα, protein degradation, Polygonatum sibiricum, exosome-like nanoparticles, drug delivery, nanomedicine, ubiquitin-proteasome system, AKT signaling, MMP2, targeted therapy