Overcoming refractory pancreatic cancer through long-term starvation therapy

The Innovation Center of NanoMedicine (Center Director: Prof. Kazunori Kataoka, Location: Kawasaki City; Abbreviation: iCONM) announces that a paper titled “Transparent cloaks independent of three-dimensional stability enable starvation therapy for intractable cancers using nanomedicines” summarizing one of its research achievements for tackling intractable cancers, was published online in the academic journal Nature Biomedical Engineering (Note 1) at 4PM on October 31, 2025 (GNT).

After intravenous injection, pharmaceuticals travel through the bloodstream to the affected area where they exert their effects. However, a significant portion is eliminated via the kidneys into urine or via the liver into bile, or undergoes chemical structural changes through metabolism, resulting in a limited amount actually reaching the target site. Nanomedicine aims to improve the efficiency of conventional drug therapy by encapsulating drugs within carriers (nanomicelles/nanomachines) measuring tens of nanometers in size. This allows a greater quantity of the drug to be delivered and concentrated at the target site. However, these nanomachines are also recognized as foreign bodies by the body and can be attacked and destroyed by immune cells. Therefore, to keep nanomachines within the body for as long as possible, stealth technology is necessary to evade the body's strict immune surveillance system. For example, stealth coating (invisibility cloak) using polyethylene glycol (PEG) to cover the exterior is widely employed. However, to apply nanomedicine as a “starvation therapy” that depletes nutrients essential for cancer cell growth, it is necessary to develop nanomachines with longer in vivo half-lives. This paper reports on the stealth effect achieved in the block copolymer, a constituent unit of the nanomachine, via an ion-pair network composed of polycation and polyanion. We demonstrated that increasing crosslinking between constituent polyions beyond a specific threshold reduces protein adsorption and macrophage uptake, enabling in vivo circulation with a half-life exceeding 100 hours. Based on this, we attempted to deliver a nanomachine equipped with asparaginase, which degrades L-asparagine essential for cancer cell growth, to cancer tissue by stealthing it with a semi-permeable ion-pair network. The extended half-life in circulation induced sustained asparagine starvation, improving treatment outcomes for metastatic breast (Note 2) and pancreatic cancers (Note 3). These findings are expected to open new avenues for improving the pharmacokinetics of nanomaterials for therapeutic drug delivery by meticulously designing stable intermolecular structures.

＜Novelty of This Study＞

1. A PEG-independent “stealth cloak” built from an ion-pair network. Instead of relying on steric repulsion (e.g., PEGylation), we stabilize the nanocarrier surface by crosslinking polyanions and polycations into a stable ion-pair network sheath that minimizes non-specific interactions (protein adsorption, macrophage uptake). This mechanism achieved extended in vivo circulation with a half-life >100 h.
2. From “more drug in” to “reshape the environment”. The long-circulating, enzyme-loaded stealth nanoreactor (asparaginase) persistently depletes L-asparagine, starving tumors systemically—a therapeutic mode previously confined mainly to hematologic cancers—thereby sensitizing solid tumors.
3. Challenging pancreatic cancer by relieving stromal barriers. In the KPC pancreatic cancer model, asparagine starvation by stealth nanoreactors alleviated desmoplasia (reduced ECM/CAF markers) and enabled broad extravasation and accumulation of anti-PD-1 antibodies across tumor tissue, thereby improving immunotherapy.
4. Conceptual advance: stealth nanoreactors as in-body nanomachines. The study reframes nanomedicine from “delivery to the tumor” to “in-body nanomachines” that recondition the tumor ecosystem and further open a path for other therapeutics.

＜Future Contributions to Society＞

1. Broader reach of metabolism-modulating therapies. A platform that keeps therapeutic enzymes active in the bloodstream for days can extend “starvation therapy” beyond hematologic cancers to hard-to-treat solid tumors.
2. Enabling immunotherapy in pancreatic cancer. By softening dense stroma, the approach can allow immune checkpoint antibodies to work where they typically fail, pointing to combination regimens that improve outcomes in highly refractory cancers.
3. Generalizable stealth design. The ion-pair network suggests a materials-agnostic route to non-fouling, long-circulating nanomedicines without depending on PEG’s steric barrier—useful for future drug delivery, diagnostics, and enzyme therapies.
4. Clinical translation pathway. Because the mechanism targets systemic metabolism and microenvironment rather than specific tumor accumulation, it simplifies translation across cancer types and reduce the need for precision targeting in some settings.

This research is being conducted with support from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the Japan Science and Technology Agency (JST) under the “Co-creation Initiative for New Technologies and Industries (COI-NEXT)” program.

Note 1: Nature Biomedical Engineering　：Launched in January 2017 as an online-only journal focused on medical engineering, it is the sister publication of Nature, which has positioned itself as an international scientific journal since its founding in 1869. Its 2024 impact factor is 26.3.

https://www.natureasia.com/ja-jp/natbiomedeng/about#journals

Note 2: Breast cancer is now the most commonly diagnosed cancer, and mortality among Japanese women continues to rise, in contrast to the decline seen in Western countries since the 1990s. Mortality is mainly due to metastatic disease. Triple-negative breast cancer (TNBC) is particularly aggressive, with high metastatic potential and poor prognosis; the five-year survival rate for metastatic TNBC is only ~12%.

Note 3: Pancreatic cancer is among the deadliest malignancies, with a 5-year survival rate of less than 10%. Even advanced immunotherapies such as anti-PD-1 antibodies generally fail, largely because the dense stromal barrier surrounding tumors prevents drugs from penetrating effectively.