Lipid nanoparticle immunotherapy restores T-cell function and eradicates solid tumours in preclinical models

A University of Pennsylvania study has demonstrated that a dual-action lipid nanoparticle can reverse T-cell exhaustion and eliminate solid tumours in mice, offering a potentially generalisable approach to cancer immunotherapy without patient-specific engineering

Engineers at the University of Pennsylvania, Philadelphia, USA, have developed a novel lipid nanoparticle platform that could serve as a broadly applicable immunotherapy for solid tumours, including cancers of the breast, liver and colon. The study has addressed a central limitation in cancer immunotherapy – the progressive exhaustion of T cells, which undermines their capacity to sustain an effective anti-tumour response within the tumour microenvironment.

T cells, a subset of white blood cells, play a critical role in immune surveillance by identifying and eliminating malignant cells through antigen recognition and cytotoxic activity. Within solid tumours, however, this process becomes compromised. Tumours create a metabolically restrictive and immunosuppressive environment characterised by nutrient depletion and inhibitory signalling molecules. Among these is indoleamine 2,3-dioxygenase, an enzyme that suppresses T-cell activity and contributes to immune evasion. Sustained exposure to these conditions leads to T-cell exhaustion, marked by reduced proliferation, diminished cytokine production and impaired cytotoxic function.

The research team has designed a lipid nanoparticle that addresses these mechanisms simultaneously. The system delivers a small-molecule inhibitor of indoleamine 2,3-dioxygenase alongside messenger RNA encoding interleukin-12, a cytokine that promotes immune activation. By combining both modalities within a single construct, the nanoparticle removes immunosuppressive signalling and restores T-cell metabolic and functional capacity. This dual-action approach has enabled reinvigoration of exhausted T cells without the need for personalised antigen targeting, which has traditionally constrained scalability and increased cost.

“Traditionally, immunotherapies have been highly specific,” said Dr. Michael J. Mitchell, Associate Professor in Bioengineering and senior author of the study published in Nature Nanotechnology.

“This more general approach works by simply re-energising T cells, whose exhaustion has been a bottleneck for developing solid-tumour immunotherapies,” he said.

Conventional lipid nanoparticles have functioned primarily as delivery vehicles for nucleic acids. In contrast, the Penn team has integrated therapeutic activity directly into the nanoparticle structure. The researchers chemically conjugated the indoleamine 2,3-dioxygenase inhibitor to the ionisable lipid component, which facilitates cellular uptake and endosomal escape. This design has created a prodrug lipid nanoparticle, in which the delivery vehicle itself contributes to therapeutic function. Previous work has attached small molecules to auxiliary components such as cholesterol, but this study represents the first report of conjugation to the ionisable lipid core.

“By building the drug directly into the lipid, we created a single, unified therapeutic system,” said Dr. Jinjin Wang, postdoctoral fellow in bioengineering and co-author of the study.

“The lipid does not just help deliver a therapy, it becomes part of the therapy, too.”

The platform has demonstrated strong efficacy in preclinical models. In vitro experiments showed that the nanoparticles induced higher expression of interleukin-12 than conventional lipid nanoparticle systems. In murine models of colon cancer, treatment led to near-complete tumour regression within 30 days and prevented recurrence, which indicates the establishment of immunological memory. Mice that received either component alone exhibited only partial tumour control, which underscores the importance of co-delivery within a single nanoparticle.

“Inside a solid tumour, T cells are like cars trying to drive with one foot on the brake and almost no fuel in the tank,” said Dr. Qiangqiang Shi, postdoctoral fellow in bioengineering and co-first author.

“These particles release the brake and refuel the T cells at the same time.”

Immunophenotypic analysis showed that treated tumours contained increased infiltration of CD8-positive cytotoxic T cells, reduced numbers of regulatory T cells and decreased expression of programmed cell death protein 1, a marker of T-cell exhaustion. Tumours that would otherwise evade immune detection acquired an inflamed phenotype, often described as ‘hot’, which is associated with improved responsiveness to immunotherapy.

The study has also reported systemic immune effects. In mice bearing bilateral tumours, local administration into a single tumour site resulted in regression of untreated tumours at distant sites. Animals that cleared their tumours resisted subsequent tumour rechallenge, which suggests durable immune memory.

“We were targeting one tumour, but we saw immune activity throughout the body,” said Shi.

“That told us the treatment was not just acting locally; it was retraining the immune system,” he added.

Safety profiling indicated that intratumoral administration achieved strong therapeutic effects with minimal toxicity. By contrast, intravenous delivery produced moderate tumour suppression but increased circulating inflammatory cytokines and markers of hepatic stress, which are known limitations of interleukin-12-based therapies. These findings highlight the importance of delivery route in balancing efficacy and safety.

Although the platform remains at a preclinical stage, the researchers have begun to explore strategies to enhance translational potential. These include expansion of the messenger RNA payload to encode alternative immunostimulatory proteins and optimisation of chemical linkers that respond to tumour-specific conditions such as acidity, enzymatic activity or oxidative stress. Efforts to improve systemic delivery are also under way, including the incorporation of tumour-targeting ligands to reduce off-target accumulation in the liver and enhance selective uptake following intravenous administration.

“Our platform is designed to be adaptable.

“We have shown it can restore immune function inside solid tumours. The next step is to refine and expand it so that it can be safely and effectively translated to the clinic,” concluded Mitchell.

For further reading please visit: 10.1038/s41565-025-02102-z