Nanoparticle-Induced Complement Activation: Implications for Cancer Nanomedicine

Abstract

Nanoparticle-based anticancer medications were first approved for cancer treatment almost 2 decades ago. Patients benefit from these approaches because of the targeted-drug delivery and reduced toxicity, however, like other therapies, adverse reactions often limit their use. These reactions are linked to the interactions of nanoparticles with the immune system, including the activation of complement. This activation can cause well-characterized acute inflammatory reactions mediated by complement effectors. However, the long-term implications of chronic complement activation on the efficacy of drugs carried by nanoparticles remain obscured. The recent discovery of protumor roles of complement raises the possibility that nanoparticle-induced complement activation may actually reduce antitumor efficacy of drugs carried by nanoparticles. We discuss here the initial evidence supporting this notion. Better understanding of the complex interactions between nanoparticles, complement, and the tumor microenvironment appears to be critical for development of nanoparticle-based anticancer therapies that are safer and more efficacious.

Platelet-Inspired Intravenous Nanomedicine for Injury-Targeted Direct Delivery of Thrombin to Augment Hemostasis in Coagulopathies

“…In a third assay, the "VBP + CBP"decorated nanoparticles (t-LNPs) were evaluated via ELISA for their ability to activate complement C3 to C3a, as this would indicate a systemic complement-mediated immunological risk. 63 As is shown is Figure 3C, the C3a/C3 ratio in plasma remained similar to the baseline (saline), on incubation with control nanoparticles or t-LNPs, indicating that in vivo these particles would have minimal complement activation risks. In a fourth assay, the control particles as well as t-LNPs were evaluated for their ability to activate neutrophils, because this would indicate an unwanted stimulation of the innate immune defense mechanism.…”

Lemon‐Derived Extracellular Vesicles Nanodrugs Enable to Efficiently Overcome Cancer Multidrug Resistance by Endocytosis‐Triggered Energy Dissipation and Energy Production Reduction

“…enhance the intracellular uptake (Figure 1e,f; Figures S7,S8, Supporting Information). According to the intracellular trafficking of EVs, [26][27][28][29] HRED and ED entered into lysosomes or cytoplasm after they internalized into cells, thus some of DOX from HRED or ED was degraded in lysosomes, and other DOX was released into the cytoplasm. Laser confocal microscopy images of ED and HRED in SKOV3/DOX and SKOV3 cells also showed that EVs or HRE (PKH67 labeled, green fluorescence) located in cytoplasm and red signal of DOX mainly distributed in nucleus.…”

Synthetic Glyconanoparticles Modulate Innate Immunity but Not the Complement System

“…Although sometimes beneficial in prophylactic protection, uncontrolled complement activation is harmful and contributes to disease progression . In cancer therapeutics, complement activation by nanoparticles has several implications and gold nanoparticles are also known to interact with the complement system. − To be used as an immunotherapeutic these glyconanoparticles must not induce complement-mediated anaphylaxis. Thus, we sought to study the effect of the mannosylated glycogold nanoparticles of the complement system.…”