Study reveals molecular rules governing the biological identity of nanoparticles

A new study has revealed molecular rules governing how nanoparticles interact with biological systems, showing how their physicochemical properties shape protein corona (PC) formation and influence biological outcomes. The findings provide a framework for designing nanomedicines with more predictable biological identities.

The study was conducted sby a research team led by Prof. LIU Yuan from the Hangzhou Institute of Medicine (HIM) of the Chinese Academy of Science (CAS). The findings were published in PNAS on October 26.

Nanoparticles hold significant promise for precise drug delivery and modern therapeutics. Yet, how do nanoparticles truly interact with biological systems in vivo? For the past two decades, the PC has been regarded as a critical determinant of the fate of nanomedicines in vivo, but it has been studied largely through empirical descriptions rather than generalizable molecular rules. Therefore, a central challenge is to determine how a nanoparticle’s physicochemical properties influence its corona to drive distinct biological outcomes.

To address this challenge, the researchers established a comprehensive Literature-Mined Nanoparticle Protein Corona Database (LM-NPC-DB) by analyzing more than 2,400 publications. This database outlined the prevailing framework linking nanoparticle properties, PC composition, and biological responses, while revealing fragmented and inconsistent proteomics data across studies.

The researchers then constructed a standardized, high-quality In-House Nanoparticle Protein Corona Database (IH-NPC-DB) covering 42 different nanomaterials with variations in key physicochemical properties, including surface charge, PEGylation, morphology, and material composition. The researchers profiled their PCs under a unified workflow. The resulting IH-NPC-DB identified 4,465 proteins, providing a comprehensive and comparable PC proteomic profile.

Leveraging the standardized IH-NPC-DB, the researchers revealed the following general molecular selection rules governing PC formation and identified their biological consequences:

Surface charge regulates cellular uptake. Anionic nanoparticles specifically recruit adhesion proteins to promote Itgav-mediated endocytosis, establishing a causal link between nanoparticle charge, PC composition, and receptor-mediated uptake.

PEGylation also promotes immune evasion by selectively depleting specific complement and coagulation factors, rather than merely preventing protein adsorption.

Nanoparticle geometry, meanwhile, imposes structural constraints and selects proteins based on specific physicochemical features, such as lysine content.

Beyond gaining these mechanistic insights, the researchers found that material-specific PCs can rebalance the serum proteome, thereby enabling the detection of low-abundance disease biomarkers.

According to the researchers, this work transforms the PC from an empirical variable into a programmable design element, shifting nanomedicine from empirical description toward rule-based rational design and providing a foundational framework for engineering nanomedicines with predictable, programmable biological identities.