Journal of controlled release : official journal of the Controlled Release SocietyMay 22, 2026

Lipid nanoparticles that mimic cells to change immune cells for cancer treatment

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated May 24, 2026

Abstract

Intratumoral administration of the Mac LNP platform significantly suppressed tumor growth in a 4 T1 breast cancer model.

The Mac LNP platform targets tumor-associated macrophages with enhanced selectivity compared to non-target cells.
Co-encapsulation of a TLR9 agonist and STAT3 siRNA promotes the conversion of macrophages from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype.
Treatment resulted in a marked increase in the M1/M2 ratio within the tumor microenvironment.
Enhanced infiltration of cytotoxic CD8T cells was observed following administration of the Mac LNPs.
The platform demonstrated tumor-agnostic applicability in an independent CT26 murine colorectal cancer model.

Simplified

Tumor associated macrophages (TAMs) predominantly exhibit an immunosuppressive M2 like phenotype within the tumor microenvironment (TME), hindering the efficacy of cancer immunotherapy. To address this, we developed a dual biomimetic macrophage targeting lipid nanoparticle (Mac LNP) platform for robust M2 to M1 reprogramming. By integrating triglycerides and phosphatidylserine to mimic chylomicrons and apoptotic bodies, respectively, the Mac LNP achieved superior selectivity for macrophages over non-target cells. This platform co-encapsulated a TLR9 agonist (CpG-ODN) and STAT3 siRNA to synergistically drive M1 polarization while silencing the master transcription factor that sustains the M2 state. In a 4 T1 syngeneic breast cancer model, intratumoral administration of Mac LNPs significantly suppressed tumor growth and remodeled the immune landscape, as evidenced by a markedly increased M1/M2 ratio and enhanced infiltration of cytotoxic CD8T cells. Cross-model validation in an independent CT26 murine colorectal cancer model further confirmed the tumor-agnostic applicability of this platform. Our findings establish the Mac LNP system as a precision framework for macrophage targeted RNA therapeutics, effectively modulating innate immunity to overcome the immunosuppressive barriers of the TME. +

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Declaration of competing interest The authors declare that they have no competing interests.

PubMed

Lipid nanoparticles that mimic cells to change immune cells for cancer treatment

Abstract

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Competing interests

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Abstract

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