Nanoparticles and cytokine response

Abstract

Synthetic nanoparticles (NPs) are non-viral equivalents of viral gene delivery systems that are actively explored to deliver a spectrum of nucleic acids for diverse range of therapies. The success of the nanoparticulate delivery systems, in the form of efficacy and safety, depends on various factors related to the physicochemical features of the NPs, as well as their ability to remain "stealth" in the host environment. The initial cytokine response upon exposure to nucleic acid bearing NPs is a critical component of the host response and, unless desired, should be minimized to prevent the unintended consequences of NP administration. In this review article, we will summarize the most recent literature on cytokine responses to nanoparticulate delivery systems and identify the main factors affecting this response. The NP features responsible for eliciting the cytokine response are articulated along with other factors related to the mode of therapeutic administration. For diseases arising from altered cytokine pathophysiology, attempts to silence the individual components of cytokine response are summarized in the context of different diseases, and the roles of NP features on this respect are presented. We finish with the authors' perspective on the possibility of engineering NP systems with controlled cytokine responses. This review is intended to sensitize the reader with important issues related to cytokine elicitation of non-viral NPs and the means of controlling them to design improved interventions in the clinical setting.

Keywords: biocompatibility; cytokine response; inflammatory response; nanoparticle; non-viral delivery.

FIGURE 1

A schematic representation of various constituents of a NP. The NPs are constructed from several types of building blocks with, if necessary, targeting moieties (for active targeting to a cell/site), coating groups (to reduce opsonization and/or non-specific interactions) and nuclear localization signals (for cell nucleus targeting). The lipid constituents of the NP could further facilitate membrane fusion and/or destabilization of endosomal membranes to prevent endosomal entrapment of the cargo.

FIGURE 2

Main pharmacological agents employed to control cytokine storm in a clinical setting. The mediators targeted by the pharmacological agent is shown in parenthesis. The immunosuppressive properties of the corticosteroids are attributed to their ability to bind glucocorticoid receptors to block various signaling pathways affecting cytokine production in immune cells. The humanized antibody Tocilizumab predominantly used in treating rheumatoid arthritis also received approval to address cytokine release syndrome (CRS) following a CAR-T therapy based on AAV (Le et al., 2018). The kinase inhibitors with indicated target enzyme displayed immuno suppressive properties, including suppression of CRS, some of which are being investigated in T-cell therapies (Fraietta et al., 2016; Huarte et al., 2020; Xiang et al., 2022). Etanercept and Anakinra was successfully used to address CRS in patients without altering the therapeutic effect of CAR-T therapy in treatment of multiple myeloma (Zhang L et al., 2021) and B-cell lymphoma (Strati et al., 2020), respectively. Other molecules such as cyclosporin and tacrolimus, which inhibit the phosphatase calcineurin, can downregulate the IL-2 cytokine levels (Chu and Ng, 2021).

FIGURE 3

Cytokine response to various formulations of PEI in preclinical animal models. The specific cytokine investigated, the administration route (IV, IP, AER; intravenous, intraperitoneal and aerosolized, respectively) and the normal/disease model employed are indicated for each study. L: Linear PEI, B: Branched PEI. The numbers on the horizontal axis indicate the molecular weight (kDa) of the PEI used. The nature of the nucleic acid cargo, the dose administered and the N:P ratio employed in the formulations were variable; this information is provided below the graph and numbered according to the bar number from left to right. References for the studies are: [1]: Zhang et al., 2013, [2]: Kawakami et al., 2006, [3]: Gautam et al., 2001, [4]: Bonnet et al., 2008, [5]: Cheng et al., 2018.

FIGURE 4

Secretion of inflammatory cytokines (TNF-α, IL-6 and IFN-γ) from PBMCs obtained from 6 separate, healthy donors in culture. The cells were treated with PMA/IO combinations at indicated concentrations and cytokine secretion was determined 3 days afterwards (by specific ELISAs). Untreated cells served as the reference. Note that some PBMCs were unresponsive to the stimulation (especially in IL-6 and TNF-α secretion) while other PBMCs were hyper-sensitive to the stimulation. Significant donor-to-donor variation was evident among the PBMCs when it comes to cytokine secretion upon the stimulation (Meenakshi Sundaram et al., 2022).

FIGURE 5

Attempts to implement RNAi in various disease models involving cytokine mediators. The specific siRNA target and the delivery system used are indicated. The references to the specific study are numbered as follows: 1: (Azzam, El Safy, et al., 2020). 2: (Bai et al., 2022). 3: (Cardoso et al., 2010). 4: (Chen et al., 2013). 5: (Diao et al., 2019). 6: (Fihurka et al., 2022). 7: (Frede et al., 2016). 8: (Frede et al., 2017. 9: (Heo et al., 2015). 10: (Herman et al., 2015). 11: (Jiang et al., 2018). 12: (Khoury et al., 2008). 13: (Kim and Kim, 2007). 14: (Kim et al., 2010). 15: (Lee et al., 2021). 16: (Lian et al., 2019). 17: (Okuda et al., 2018). 18: (Pandi et al., 2018). 19: (Peer et al., 2008). 20: (Rudd et al., 2020). 21: (Kim et al., 2011). 22: (Shi et al., 2018). 23: (Shin et al., 2020). 24: (Tang et al., 2022). 25: (Wu et al., 2018). 26: (Wu et al., 2021). 27: (Xiao et al., 2014). 28: (Xiao et al., 2016). 29: (Xiao et al., 2017). 30: (Yan et al., 2019). 31: (Yang et al., 2022). 32: (Jiang et al., 2018). 33: (Yoon et al., 2016).

FIGURE 6

The doses of siRNA treatments used in preclinical models of inflammatory diseases. (A) The dose of individual siRNA injections. (B) Total dose injected based on the individual injection dose and the numbers of injections undertaken. The data is from studies summarized in Figure 5, excluding in vitro/cell culture studies. The numbers refer to the study references shown in the legend of Figure 5. The nature of delivery system used was classidied as polymeric (blue), lipid (orange) and others (green).