Biocompatible and Bio-Orthogonal Surface Engineering of Inorganic Self-assembled Nanocrystals for Precision Drug Targeting: A Review

OBJECTIVE: Inorganic nanocrystals represent a transformative platform for targeted drug delivery, offering unique physicochemical properties derived from their crystalline cores. However, clinical translation is contingent upon sophisticated surface engineering to navigate biological barriers, ensure colloidal stability, and achieve precision targeting. SIGNIFICANCE OF REVIEW: This review critically examines the synergistic convergence of biocompatible coatings and bio-orthogonal chemistry as a paradigm shift in nanocrystal surface design. We systematically analyze advanced coating materials including polymeric (PEG, zwitterions, poly(2-oxazoline)), protein-based, and lipid architectures that establish stealth coronas against opsonization and immune clearance. Concurrently, we evaluate bio-orthogonal methodologies (SPAAC, IEDDA) enabling site-specific, catalyst-free conjugation of targeting ligands under physiological conditions. KEY FINDINGS: The integration of these approaches facilitates stimuli-responsive smart nanocrystals capable of logic-gated activation within pathological microenvironments. CONCLUSION: We further address translational challenges including long-term biocompatibility, scalable manufacturing, and regulatory pathways, proposing design principles for next-generation nanotherapeutics where interfacial chemistry dictates biological destiny.