Camouflaging Nanoparticles for Ratiometric Delivery of Therapeutic Combinations

Combination therapy is a common clinical practice in the management of malignancies. Synergistic therapeutic outcomes are achieved only when tumor cells are exposed to drugs in an optimal ratio and sequence; therefore, carriers coencapsulating multiple drugs are widely pursued for their coordinated delivery. However, it is challenging to coload drugs with different physicochemical properties in a single carrier with specific ratios. It is not even beneficial to load them in one carrier if they need to be released at different times. We propose to load drugs into chemically compatible carriers separately, equalize different carriers by a simple, rapid, and versatile camouflage technique based on natural polyphenol tannic acid (TA), and administer them in desirable ratios and sequences. To demonstrate this potential, different nanoparticles (NPs) with different charges and material basis, such as polymeric (carboxyl-terminated or amine-terminated cationic polystyrene NPs or poly(lactic- co-glycolic acid (PLGA) NPs), inorganic (mesoporous silica NPs (MSNs)), and liposomal NPs, are camouflaged with TA layers and further modified with folate-conjugated polyethylene glycol to aid in the delivery to tumors. The camouflaged NPs show similar physicochemical properties and interactions with KB cells despite the difference in core platforms, and their mixtures interact with common cell targets in a ratiometric manner. In KB-tumor-bearing mice, the camouflaged PLGA NPs and MSNs show near-perfect colocalization in tumors. These results support that TA helps equalize different NPs with high versatility and enables their ratiometric delivery to common targets. This approach can relieve technical challenges in ratiometric codelivery or sequential delivery of therapeutic agents with distinct physicochemical properties.