Nanoparticle Strategies Aim to Improve Cancer Drug Delivery

Recent studies published in Nature Materials, the Journal of the American Chemical Society, and the Journal of Controlled Release describe new nanoparticle-based strategies to improve cancer drug delivery, including microbiome modulation, mRNA vaccines, and engineered lipid nanoparticles. The approaches aim to increase drug accumulation in tumors, reduce side effects, and overcome drug resistance.

In one study led by researchers at The University of Texas MD Anderson Cancer Center, reshaping the gut microbiome with a short course of the antibiotic metronidazole roughly doubled how long nanoparticle-based chemotherapy remained in circulation, increased drug accumulation in tumors, and improved survival across multiple cancer types in preclinical models. Gut bacteria send chemical signals to liver Kupffer cells through bile acids; when metronidazole reduced certain gut bacteria, bile acid levels dropped, causing Kupffer cells to shift into a "quiet" state and clear fewer nanomedicine particles. Fecal microbiota transplantation confirmed the effect was driven by the microbiome itself rather than residual antibiotic. Metronidazole is already approved by the Food and Drug Administration.

A study from RCSI University of Medicine and Health Sciences provided the first preclinical proof-of-concept for an mRNA vaccine targeting neuroblastoma, the deadliest form of childhood cancer. The vaccine uses self-assembling peptide nanoparticles to deliver mRNA that trains the immune system to recognize Glypican 2 (GPC2), a protein heavily expressed on neuroblastoma cells. In preclinical models, the vaccine reduced tumor size by 70% and delayed tumor development by 10–11 days. Neuroblastoma accounts for 15% of all childhood cancer deaths, and 80% of high-risk patients show little response to standard treatments.

Adelaide University researchers developed a hybrid nanoparticle 'delivery vehicle' made from lipids and polymers that encapsulates the lung cancer drug RB-012. The nanoparticles increased the drug's bioavailability by more than 30-fold while reducing exposure to healthy organs. In preclinical testing, the nanoparticle-delivered drug showed stronger tumor-killing effects compared to the drug alone. The research was funded by Cancer Council SA and Tour de Cure.

An international team led by Tohoku University engineered porous amino acid nanoparticles that sequentially release the P-gp inhibitor quinidine before the anticancer drug doxorubicin, disabling the drug efflux mechanism that drives multidrug resistance. Combined with photothermal therapy using near-infrared laser light, the approach achieved complete tumor elimination and 100% survival in a mouse model of drug-resistant cancer, with no detectable toxicity to normal tissues. The findings were published in the Journal of Controlled Release.

Two studies from the University of Pennsylvania redesigned lipid nanoparticles (LNPs) to improve mRNA delivery. In one study published in the Journal of the American Chemical Society, researchers added aromatic rings to the ionizable lipid to create "aroLNPs." The best-performing aroLNPs delivered tenfold less mRNA to the liver than the LNP formulation used in the Moderna COVID-19 vaccine while maintaining lymph node delivery, increasing the lymph-node-to-liver ratio by five- to tenfold. They generated antibody responses comparable to clinically approved formulations and caused minimal increases in systemic inflammatory cytokines. In a separate study published in Nature Materials, researchers used imidoester cross-linkers to create the lipid C12-2aN, which reprogrammed dendritic cell metabolism by increasing glycolysis and lactate production. Compared to an FDA-approved formulation, these LNPs delivered more than three times as much mRNA to lymph nodes relative to the liver, reduced inflammatory markers in the bloodstream, and caused smaller increases in body temperature in mice.

The findings indicate that nanoparticle engineering can improve both the delivery and tolerability of cancer therapies, and the approaches may extend to other applications such as vaccines and autoimmune-disease treatments.