Beyond the bactericidal or bacteriostatic effects that were described in the early days of nanomedicine, an interesting field of research is related to the long-term effect of NP exposure on trained innate immunity (12, 13). Swartzwelter et al. report how gold nanoparticles (AuNPs) loaded with different microbial molecules differentially reprogram macrophage responses which downregulate or exacerbate innate immune memory. Although the molecular mechanisms underlying how AuNPs modulate innate memory are unknown, it appears to be defined by the pathogenic agent and the individual’s immune history, independently of the primary response elicited by AuNPs. An often understudied issue is the linking of initiation, progression and resolution of inflammation with the effect of NPs on functional responses by macrophages. Sun et al. describe a tryptophan-containing hexapeptide-coated AuNP with opposite immunomodulatory activities in resting and TLR-stimulated macrophages, targeting NF-κB or IRAK downstream signalling, respectively. Korshoj et al. provide an insightful review on how to tackle chronic infections in the central nervous system by modulating macrophage/microglia polarization using different NP platforms. Finally, Ernst and Puntes comment on the role of oxidative metabolism in macrophage function and the potential of regulatory interventions trough cerium oxide NPs. Interestingly, it is worth mentioning that inorganic or metallic core NPs are attracting more attention compared to the reluctance they triggered a few years ago because of their potential toxicity.

The review by Mulens-Arias et al. provides a comprehensive account of our current understanding on the effects of Iron Oxide Nanoparticles (IONPs) on macrophage reprogramming in the tumour microenvironment, including effects on the interactions between malignant and non-transformed cells. Garland et al. explore the capacity of cytosolic double-stranded DNA to promote antitumor immunity by activating the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), which drive the production of type I interferons and other inflammatory cytokines. A major bottleneck to activate the cGAS/STING cytosolic pathway with double-stranded DNA is the combination of both deoxyribonuclease activity and endosomal escape, which forced the development of direct STING activators. To overcome the limitation of a non-physiological stimulation of cGAS-STING signaling, Garland et al. identified in a DNA library screening a DNA-based polymeric nanoparticle with enhanced features in terms of stability and functional activation of the cGAS-STING pathway. In vitro and in vivo experiments demonstrated the feasibility of directly targeting cGAS to reprogram macrophages in tumors, opening new venues for cancer immunotherapy. Alongside, Dey et al. provide further information on the impact of nucleic acid cargo in cationic lipid-based delivery systems aimed to induce macrophage and dendritic cell modulation. Finally, Makhijani and McGaha review the role of exosomes in myeloid immune cells. These nano-sized vesicles of endosomal origin (30-150 nm in diameter) are the smallest type of extracellular vesicles, whose role in cancer immunology and inflammatory/autoimmune diseases has only recently started to be fully appreciated.

The review by Solé and Santamaría focuses on the reprogramming capabilities of NPs to generate antigen-specific T-regulatory type 1 (Tr1)-like cells. They pay special attention to Tr1-like cell heterogeneity and its potential molecular characterization. By using dendritic mesoporous silica nanoparticles, An et al. report the synthesis and characterization of a peptide-based delivery platform as a vaccination strategy towards foot-and-mouth disease virus. Also in the field of modified platforms for new vaccination strategies, Feola et al. exploit oncolytic viruses as in situ cancer vaccines. In this work, they developed an alternative approach to generate oncolytic adenovirus functionalised with tumour antigens in order to obtain sustained T cell responses while avoiding non-scalable procedures.

Authors listed have made a direct and intellectual contribution to the editorial and approved for publication.

DP is supported by the Regional Ministry of Transformación Económica, Industria, Conocimiento y Universidades, PAID2020, CTS677 to DP) and the Spanish Government Ministry of Science and Innovation of Spain [RTI2018-098432-B-I00, co-funded by the European Regional Development Fund (ERDF), a way to build Europe]. FQ is supported by the National Institutes of Health, the Progressive Multiple Sclerosis Alliance and the National Multiple Sclerosis Society.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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