Stealth Strategies for Cancer Nanomedicine: A Review of Immune Evasion and Tumor Targeting

Nanocarrier platforms can improve cancer therapy through enhanced selectivity and reduced systemic toxicity. Yet mononuclear phagocyte system (MPS) clearance sharply limits delivery; in preclinical models, often less than 1% of the injected dose reaches tumors. Surface-engineering strategies that let nanocarriers evade immune recognition have emerged to prolong circulation and improve therapeutic outcomes. These fall into two families: synthetic coatings, including PEG grafting and zwitterionic polymers, and biomimetic approaches, including cell-membrane cloaking (red blood cell, cancer cell, and immune cell membranes) and molecular immunomodulation. This review examines both. PEGylated liposomes remain the clinical gold standard with 55-h circulation in humans, though anti-PEG immunity and complement activation-related pseudoallergy (CARPA) represent ongoing challenges. Membrane-coated carriers borrow nature’s own stealth mechanisms, such as CD47-mediated “don’t eat me” signaling, to achieve prolonged circulation and, in specific preclinical comparisons, half-lives exceeding those of matched PEG-coated controls. They also avoid the anti-polymer antibody responses associated with PEG. Despite favorable preclinical data, clinical translation of second-generation biomimetic platforms remains stalled due to manufacturing complexity, regulatory uncertainty, and insufficient differentiation from existing FDA-approved therapies. This review critically evaluates pharmacokinetic and biodistribution outcomes, immunogenicity profiles, and translation barriers, while identifying scalable manufacturing protocols and regulatory engagement as prerequisites for realizing the clinical potential of biomimetic nanocarriers in oncology.