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Updated: Jun 10, 2026
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Tumor-Specific Delivery of CD28 siRNA via Lyso-PC C-16 Modified Lipid Nanoparticles Overcomes Anti-PD-1 Resistance by
Yangyang Chai1, Keyu Wang2, Jiali Fang1
1State Key Laboratory of Medicinal Chemical Biology, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, P. R. China.
Abstract:
Uncovering novel targets that synergize with immune checkpoint blockade (ICB) is an urgent clinical priority. While cancer cell-intrinsic CD28 facilitates immune escape by functioning as a non-classical RNA-binding protein to stabilize CD274 (PD-L1) mRNA, inhibiting this pathway in cancer cells without impairing essential T cell CD28 costimulation remains a major structural challenge. Here, we report the development of a 16:0 LPC-modified SM102-based lipid nanoparticle (LPC-LNP) that exploits altered tumor lipid metabolism for highly selective cancer cell transfection. By leveraging elevated lysophosphatidylcholine acyltransferase (LPCAT) uptake mechanisms inherent to malignant cells, LPC-LNPs efficiently deliver Cd28 small interfering RNA directly to tumor cells while strictly avoiding T cell sequestration. In vivo administration of LPC-LNP-Cd28 successfully knocked down 80% of cancer cell CD28, substantially reduced PD-L1 expression, and circumvented the off-target immunosuppression observed with commercial lipid formulations. Consequently, targeted Cd28 silencing reshapes the immunosuppressive tumor microenvironment, augmenting twofold CD8+ T cell infiltration and dendritic cell activation to extend survival in murine breast and lung cancer models to 1.3-1.5 folds. Furthermore, the combined use of LPC-LNP-Cd28 effectively eradicates resistance to anti-PD-1 therapy. This study provides a highly translatable, cancer-specific nanomedicine platform, confirming that selectively antagonizing tumor-intrinsic CD28 holds profound promise for advanced cancer immunotherapy.
Insights
Researchers developed a novel lipid nanoparticle (LNP) to selectively target cancer cells. This therapy reduces PD-L1 expression and enhances anti-tumor immunity, improving survival in preclinical cancer models.
Area of Science:
- Oncology
- Immunology
- Nanomedicine
Background:
- Immune checkpoint blockade (ICB) is a key cancer therapy, but novel synergistic targets are needed.
- Cancer cell-intrinsic CD28 promotes immune escape by stabilizing PD-L1 mRNA.
- Targeting cancer cell CD28 without affecting T cell costimulation is a challenge.
Purpose of the Study:
- To develop a cancer-specific nanomedicine for selective CD28 inhibition in tumor cells.
- To assess the efficacy of this approach in preclinical cancer models.
Main Methods:
- Developed a 16:0 LPC-modified SM102-based lipid nanoparticle (LPC-LNP) for targeted delivery.
- Utilized elevated lysophosphatidylcholine acyltransferase (LPCAT) uptake in cancer cells for selective transfection.
- Delivered Cd28 small interfering RNA (siRNA) specifically to tumor cells, avoiding T cells.
Main Results:
- LPC-LNP-Cd28 achieved 80% knockdown of cancer cell CD28 and reduced PD-L1 expression.
- This approach avoided off-target immunosuppression seen with other lipid formulations.
- Demonstrated a twofold increase in CD8+ T cell infiltration and dendritic cell activation.
- Extended survival by 1.3-1.5 folds in murine breast and lung cancer models.
- Overcame resistance to anti-PD-1 therapy when used in combination.
Conclusions:
- Selective antagonism of tumor-intrinsic CD28 using LPC-LNPs is a promising strategy for cancer immunotherapy.
- This nanomedicine platform offers a translatable approach to enhance ICB efficacy and overcome resistance.
