Side effects and toxicity of nanoparticles in cancer treatment

Abstract

Nanomedicine has reshaped cancer therapeutics by enabling tumor-selective delivery, controlled release, and multimodal combinations with imaging, immunotherapy, and gene editing. The physicochemical tunability of nanoparticles (NPs), including size, shape, surface chemistry, and responsiveness to biological stimuli, permits improved pharmacokinetics and intratumoral accumulation via passive (EPR) and active targeting. Yet these same attributes underlie distinct safety liabilities. This chapter synthesizes current knowledge on NP classes (organic, inorganic, and carbon-based), their structure, properties, function relationships, and the determinants of bioavailability and toxicity. We review mechanisms of adverse outcomes encompassing protein-corona–mediated biodistribution shifts, immunotoxicity (complement activation, cytokine release), oxidative and nitrosative stress, organelle dysfunction, and regulated cell-death programs including pyroptosis, ferroptosis, necroptosis. Particular attention is paid to off-target ferroptosis, inflammation in nonmalignant tissues, size- and shape-dependent hazards, and the translational implications of NP transformations and bioaccumulation. Finally, we outline a safe-by-design framework integrating degradable/stealth formulations, organelle- and pathway-specific delivery, rigorous in vitro/in vivo concordance testing, and quantitative systems toxicology. Together, these principles chart a practical path to maximize antitumor efficacy while minimizing systemic risk, accelerating the clinical maturation of precision nanomedicine.