Complement activation by drug carriers and particulate pharmaceuticals: Principles, challenges and opportunities

Considering the multifaceted protective and homeostatic roles of the complement system, many consequences arise when drug carriers, and particulate pharmaceutical formulations clash with complement proteins, and trigger complement cascade. Complement activation may induce formulation destabilization, promote opsonization, and affect biological and therapeutic performance of pharmaceutical nano- and micro-particles. In some cases, complement activation is beneficial, where complement may play a role in prophylactic protection, whereas uncontrolled complement activation is deleterious, and contributes to disease progression. Accordingly, design initiatives with particulate medicines should consider complement activation properties of the end formulation within the context of administration route, dosing, systems biology, and therapeutic perspective. Here we examine current progress in mechanistic processes underlying complement activation by pre-clinical and clinical particles, identify opportunities and challenges ahead, and suggest future directions in nanomedicine-complement interface research

Airborne Particulate Matter and SARS-CoV-2 Partnership: Virus Hitchhiking, Stabilization and Immune Cell Targeting—A Hypothesis

It is widely assumed that the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in humans occurs through close contact with an infected person, short-range transmission through respirable droplets from an infected individuals' cough or sneeze, and aerosolized airborne droplets in long-range (over a few meters) transmission (1). Large respirable droplets (>5 μm) rapidly settle out of the air, whereas virus-laden small droplets (200 signatories, has further stressed the importance of inhalation exposure to viruses in respirable droplets at short to medium distances (up to several meters) (2). In contrast to the inhalation mode of viral transmission through airborne respirable droplets, here we speculate an additional role for settled and airborne particulate matter (PM) not only in viral transmission through inhalation and ingestion, but also in promoting immunity through antigen delivery, adjuvanticity and trained immunity

Genomic perspectives in inter-individual adverse responses following nanomedicine administration: The way forward

The underlying mechanism of intravenous infusion-related adverse reactions inherent to regulatory-approved nanomedicines still remains elusive. There are substantial inter-individual differences in observed adverse reactions, which may include cardiovascular, broncho-pulmonary, muco-cutaneous, neuro-psychosomatic and autonomic manifestations. Although nanomedicine-mediated triggering of complement activation has been suggested to be a significant contributing factor to these adverse events, complement activation may still proceed in non-responders. Whether these reactions share similar immunological mechanisms and underpinning genetic factors with drug hypersensitivity syndrome remains to be investigated. Genetic association studies could be a powerful tool to dissect causative factors and reveal the multiple molecular pathways that induce infusion related adverse reactions. It is envisaged that such research may lead to the design of reliable in vitro profiling tests for risk assessment and treatment decisions, thereby revolutionizing the practice of medicine with nanopharmaceuticals. Such procedures may further improve regulatory approval processes for nanomedicines currently in the pipeline and decrease the overall cost of health care. Here we discuss some key innate immunity genes and their polymorphisms in relation to nanomedicine infusion-mediated symptomatic responses. © 2012 Elsevier B.V

Perspectives on complement and phagocytic cell responses to nanoparticles: From fundamentals to adverse reactions

: The complement system, professional phagocytes and other cells such as Natural killer cells and mast cells are among the important components of the innate arm of the immune system. These constituents provide an orchestrated array of defences and responses against tissue injury and foreign particles, including nanopharmaceuticals. While interception of nanopharmaceuticals by the immune system is beneficial for immunomodulation and treatment of phagocytic cell disorders, it is imperative to understand the multifaceted mechanisms by which nanopharmaceuticals interacts with the immune system and evaluate the subsequent balance of beneficial versus adverse reactions. An example of the latter is adverse infusion reactions to regulatory-approved nanopharmaceuticals seen in human subjects. Here, we discuss collective opinions and findings from our laboratories in mapping nanoparticle-mediated complement and leucocyte/macrophage responses