Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapyMay 14, 2026

Designing biodegradable fat-based particles that escape cell digestion to improve timed immune therapy with interleukin-15

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated May 15, 2026

Abstract

A novel treatment approach using biotin-targeted lipid nanoparticles shows potent antitumor efficacy in vivo against triple-negative breast cancer (TNBC).

Interleukin-15 (IL-15) therapy may be hindered by its sequestration due to interactions with M2-type tumor-associated macrophages.
Resiquimod (R848) can promote a shift from M2 to M1 macrophages, potentially improving the tumor immune environment.
The lipid nanoparticles are designed to encapsulate IL-15 messenger RNA and R848 for enhanced immunotherapy.
Release of R848 from the nanoparticles can lead to reprogramming of macrophages, disrupting their inhibitory interactions with tumor cells.
Subsequent release of IL-15 messenger RNA may result in sustained IL-15 expression, activating immune responses to target tumor growth.

Simplified

Interleukin-15 (IL-15) has emerged as a compelling immunostimulatory cytokine for the treatment of refractory, metastatic, and recurrent triple-negative breast cancer (TNBC). However, the crosstalk between tumor cells and M2-type tumor-associated macrophages (M2-TAMs) might lead to IL-15 sequestration, ultimately inducing resistance to IL-15 therapy in TNBC. Resiquimod (R848), a Toll-like receptor 7/8 (TLR7/8) agonist, promotes M2-to-M1 repolarization of TAMs, thereby remodeling the immunosuppressive tumor immune microenvironment (TIME). Herein, biotin-targeted, biodegradable fluorinated lipid nanoparticles (LNPs) are fabricated for compartmentalized encapsulation of IL-15 messenger RNA (IL-15 mRNA) and R848 for chronological TLR-augmented cytokine immunotherapy (TACIT), which acts through tumor immune landscape remodeling. Owing to outside-in degradation of the diselenide-bridged LNPs in the redox environment, R848 is rapidly released and transported into the extracellular space to reprogram M2-to-M1 macrophages, disrupting the inhibitory crosstalk of macrophages with tumor cells and reducing IL-15 sequestration. Subsequently, IL-15 mRNA is released to trigger sustained IL-15 expression and secretion through intracellular translation, which initiates immune responses to inhibit tumor growth. Importantly, this chronological TACIT strategy demonstrates potent antitumor efficacy in vivo across multiple TNBC models. This tailor-designed multifunctional LNP offers a pioneering avenue for advancing chronological TACIT-based treatments against TNBC by enhancing IL-15 therapy.

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

Designing biodegradable fat-based particles that escape cell digestion to improve timed immune therapy with interleukin-15

Abstract

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Competing interests

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Abstract

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