Volume 5 Number 1 2026
Engineering the Immune Interface of Targeted Nanocarriers: From Passive Stealth to Programmed Recognition
Gnanasekaran Ashok 1*, Diksha D Shroff 2 Sarah Stephenie John Sandanaraj 3
Biosensors and Nanotheranostics 5 (1) 1-8 https://doi.org/10.25163/biosensors.5110978
Submitted: 16 December 2025 Revised: 01 February 2026 Accepted: 11 February 2026 Published: 13 February 2026
Nanocarriers seldom fail because their chemistry is poor. They fail because the body reads them, and reads them quickly. Within seconds of injection a biomolecular corona assembles on every synthetic surface, and the composition of that layer, rather than the engineered surface beneath it, determines whether a particle circulates or is removed by the mononuclear phagocyte system. This review follows the consequences of that single fact across four connected literatures. We first revisit corona formation and Vroman-type exchange, where the balance of opsonins and dysopsonins sets clearance. We then trace the trajectory of stealth chemistry itself, from poly(ethylene glycol) grafting, whose protective effect depends on chain conformation and whose repeated use provokes anti-PEG antibodies and accelerated blood clearance, to polysarcosine, poly(2-oxazoline)s and zwitterionic coatings that lower phagocytic uptake seven- to fifty-two-fold without comparable immunogenicity. A third strand concerns biohybrid design, in which donor cell membranes transfer authentic self-markers, most importantly CD47, whose ligation of macrophage SIRP-alpha suppresses phagocytosis by roughly half to two-thirds while homotypic adhesion molecules confer tumour tropism. The fourth strand concerns transport. Evidence that passive enhanced permeability and retention delivers a median of about 0.7 % of injected dose, and that up to 97 % of tumour entry proceeds by active transcytosis across a specialised endothelial subset, has displaced the leakage model with an Active Transport and Retention framework. We close by linking these interfaces to CRISPR-based biosensing and artificial-intelligence liquid biopsy, where sub-attomolar detection and relapse prediction months ahead of imaging appear achievable, and by naming what remains unresolved.
Keywords: protein corona; PEGylation; zwitterionic polymers; cell membrane camouflage; CD47–SIRPα axis; active transport and retention; CRISPR biosensing; liquid biopsy
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