Nanomedicine and the innate immune system: immunogenicity, nanoparticle-immune cell interactions and implications for cancer immunotherapy
- 1National Center for Drug Research and Evaluation, Italian National Institute of Health
- 2School of Science and Technology, Chemistry Division, University of Camerino
Abstract
Nanoparticles were initially considered inert carriers for therapeutic payloads. This view has evolved substantially, as a growing body of experimental and clinical evidence indicates that engineered nanoparticles act as active immunomodulators, engaging pattern recognition receptors (PRRs), activating the complement cascade, reprogramming macrophage polarization, and inducing trained immunity in innate immune cells. This dual role of nanoparticles as both immunological agents and delivery vehicles represents a fundamental change that demands an integrative framework combining immunogenicity assessment, nanotoxicology, and therapeutic exploitation. This review provides an overview of the current state of the art at the nanomedicine–innate immunity interface across six nanoparticle classes, adopting a comparative framework that identifies both the immunological mechanisms shared among platforms and the specific features that distinguish individual nanoparticle systems. The analysis focuses on key innate immune populations, including dendritic cells (DCs), macrophages, natural killer (NK) cells, neutrophils and mast cells, as well as major innate immune signaling pathways, including the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS–STING) pathway, Toll-like receptor (TLR) signaling, and the NOD-like receptor protein 3 (NLRP3) inflammasome. The innate immune system represents a primary determinant of the biological outcome of nanomaterial exposure and provides a critical link to subsequent adaptive responses. Two methodological themes recur throughout the analysis. The first concerns attribution: distinguishing responses driven by the carrier itself from those driven by its cargo or by contaminants requires defined controls, and in their absence an observed response should not be ascribed to the nanomaterial. The second is inter-individual variability, which emerges as a determinant of outcome rather than as experimental noise, and which appears to arise from the combination of recipient and platform rather than from either alone, so that susceptibility established for one platform does not transfer to another. Our aim is to highlight unexplored connections and experimental gaps that currently limit clinical translation, offering an integrated interpretation of nanoparticle–innate immunity interactions that points to unresolved immunological challenges and oncology-relevant therapeutic opportunities for each class still awaiting validation.
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BibTeX
@article{bozzuto2026nanomedicine,
title = {{Nanomedicine and the innate immune system: immunogenicity, nanoparticle-immune cell interactions and implications for cancer immunotherapy}},
author = {Giuseppina Bozzuto and Annarita Stringaro and Sofia Migani and Marisa Colone and Annarica Calcabrini and Maria Luisa Dupuis},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1946595},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1946595/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Nanomedicine and the innate immune system: immunogenicity, nanoparticle-immune cell interactions and implications for cancer immunotherapy
AU - Giuseppina Bozzuto
AU - Annarita Stringaro
AU - Sofia Migani
AU - Marisa Colone
AU - Annarica Calcabrini
AU - Maria Luisa Dupuis
PY - 2026
DA - 2026/10/20
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1946595
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1946595/full
AB - Nanoparticles were initially considered inert carriers for therapeutic payloads. This view has evolved substantially, as a growing body of experimental and clinical evidence indicates that engineered nanoparticles act as active immunomodulators, engaging pattern recognition receptors (PRRs), activating the complement cascade, reprogramming macrophage polarization, and inducing trained immunity in innate immune cells. This dual role of nanoparticles as both immunological agents and delivery vehicles represents a fundamental change that demands an integrative framework combining immunogenicity assessment, nanotoxicology, and therapeutic exploitation. This review provides an overview of the current state of the art at the nanomedicine–innate immunity interface across six nanoparticle classes, adopting a comparative framework that identifies both the immunological mechanisms shared among platforms and the specific features that distinguish individual nanoparticle systems. The analysis focuses on key innate immune populations, including dendritic cells (DCs), macrophages, natural killer (NK) cells, neutrophils and mast cells, as well as major innate immune signaling pathways, including the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS–STING) pathway, Toll-like receptor (TLR) signaling, and the NOD-like receptor protein 3 (NLRP3) inflammasome. The innate immune system represents a primary determinant of the biological outcome of nanomaterial exposure and provides a critical link to subsequent adaptive responses. Two methodological themes recur throughout the analysis. The first concerns attribution: distinguishing responses driven by the carrier itself from those driven by its cargo or by contaminants requires defined controls, and in their absence an observed response should not be ascribed to the nanomaterial. The second is inter-individual variability, which emerges as a determinant of outcome rather than as experimental noise, and which appears to arise from the combination of recipient and platform rather than from either alone, so that susceptibility established for one platform does not transfer to another. Our aim is to highlight unexplored connections and experimental gaps that currently limit clinical translation, offering an integrated interpretation of nanoparticle–innate immunity interactions that points to unresolved immunological challenges and oncology-relevant therapeutic opportunities for each class still awaiting validation.
SN - 1664-3224
ER -