Tuning pH for the Controlled Formation of Ultrasmall Nanoparticles with Direct Cytosolic Access

Area of Science:

• Biotechnology
• Materials Science
• Nanomedicine

Background:

• Direct cytosolic delivery of nanoparticles bypasses endocytic pathways, reducing intracellular trafficking barriers.
• Ultrasmall nanoparticles (<10 nm) offer potential for membrane translocation but face drug loading and stability challenges.

Purpose of the Study:

• To develop a versatile polymer system for producing ultrasmall nanoparticles (USNPs) for direct drug delivery.
• To overcome limitations of current USNP technologies regarding drug loading and stability.

Main Methods:

• A pH-tunable polymer system was employed to generate nanoparticles (10-50 nm) with subsequent crosslinking for stability.
• Machine learning and molecular dynamics (MD) simulations were used to correlate drug properties (e.g., pK_aH) with encapsulation and nanoparticle size.
• Experimental validation confirmed direct cytosolic delivery and bypassing of the endosomal pathway.

Main Results:

• The polymer system successfully encapsulated diverse drugs into stable nanoparticles by adjusting pH.
• Machine learning identified drug pK_aH as a critical factor for encapsulation efficiency.
• MD simulations revealed USNP surface properties conducive to cell membrane interaction.
• Experimental data confirmed direct cytosolic delivery of the synthesized USNPs.

Conclusions:

• The developed platform enables facile production of ultrasmall nanoparticles for a wide range of drugs.
• This strategy provides a robust method for improved intracellular drug delivery via direct cytosolic entry.
• The findings offer a promising approach for advancing nanomedicine and drug delivery systems.