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Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The constant turnover of synovial fluid results in short residence time of administered drugs in the joint space and the dense negatively charged matrix of cartilage hinders their diffusive transport. Drugs are, therefore, unable to reach their cell and matrix targets in sufficient doses, and fail to elicit relevant biological response, which has led to unsuccessful clinical trials. The high negative fixed charge density (FCD) of cartilage, however, can be used to convert cartilage from a barrier to drug entry into a depot by making drugs positively charged. Here we design cartilage penetrating and binding cationic peptide carriers (CPCs) with varying net charge, spatial distribution and hydrophobicity to deliver large-sized therapeutics and investigate their electro-diffusive transport in healthy and arthritic cartilage. We showed that CPC uptake increased with increasing net charge up to +14 but dropped as charge increased further due to stronger binding interactions that hindered CPC penetrability and uptake showing that weak-reversible binding is key to enable their penetration through full tissue thickness. Even after 90% GAG depletion, while CPC +14 uptake reduced by over 50% but still had a significantly high value of 148x showing that intra-tissue long-range charge-based binding is further stabilized by short-range H-bond and hydrophobic interactions. The work presents an approach for rational design of cationic carriers based on tissue FCD and properties of macromolecules to be delivered. These design rules can be extended to drug delivery for other avascular, negatively charged tissues.

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High-purity milk exosomes were engineered with surface PEGylation and siRNA encapsulation for enhanced oral drug delivery.

Biological systems overwhelmingly comprise charged entities generating electrical activity that can have significant impact on biological structure and function. This intrinsic bio-electrical activity can also be harnessed for overcoming the tissue matrix and cell membrane barriers, which have been outstanding challenges for targeted drug delivery, by using rationally designed cationic carriers. The weak and reversible long-range electrostatic interactions with fixed negatively charged groups facilitate electro-diffusive transport of cationic therapeutics through full-tissue thickness to effectively reach intra-tissue, cellular, and intracellular target sites. This article presents a perspective on the promise of using rationally designed cationic biomaterials in targeted drug delivery, the underlying charge-based mechanisms, and bio-transport phenomena while addressing outstanding concerns around toxicity and methods to mitigate them. We also discuss electrically charged drugs that are currently being evaluated in clinical trials and identify areas of further development that have the potential to usher in new treatments.

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