Although arginine-rich polymers and peptides are extensively used as delivery carriers for drugs/proteins/nanoparticles, their cell delivery mechanism is not clearly understood. Recent studies show that arginine-terminated nanoparticles can enter into a cell via a nonendocytic approach that involves direct membrane penetration. However, poor colloidal stability of arginine-terminated nanoparticles under physiological conditions restricts their application potential. Here, we show that the nonendocytic cell delivery of arginine-terminated nanoparticles is controlled by their colloidal stability in the presence of phosphates. We have designed arginine-terminated quantum dots (QDs) of 10–15 nm hydrodynamic size, which enter into the cell via a nonendocytic approach, provided that they are colloidal and dispersed during cellular uptake. We have demonstrated that arginine-terminated QDs rapidly precipitate in the presence of monophosphates or polyphosphates, and polyphosphates have a stronger effect than monophosphates. Introducing polyethylene glycol at the QD surface can improve the colloidal stability against phosphates. Control experiments show that amine/ammonium-terminated cationic QDs of similar sizes do not have such a type of phosphate-dependent precipitation issue. We propose that arginine-terminated colloidal nanoparticles have a unique advantage over amine/ammonium-terminated nanoparticles as they can bind with the cell membrane phosphate via guanidinium–phosphate salt bridging. Bulk phosphate provides reversibility in this binding interaction so that nonendocytic cell uptake occurs via charge compensation of cationic nanoparticles without membrane damage. The developed surface chemistry approach and the proposed mechanisms can be adapted to other nanoparticles for efficient cell delivery and for designing delivery carriers.

Piezocatalytic materials have considerable application potential in wireless therapy. Most of these applications require biocompatible nanomaterials for in vivo targeting and control of intracellular processes. However, the piezocatalytic performance of a material decreases at a nanometer size regime, and most of the biocompatible materials have poor piezocatalytic efficiency. In particular, hydroxyapatite or calcium phosphate-based nanomaterials have weak piezocatalytic properties that limit the biomedical application potential. Here, we show that anisotropic shape and Au nanoparticle conjugation can enhance the piezocatalytic property of a calcium phosphate nanomaterial by 10 times and the performance approaches that of the bulk/nanoparticle form of well-known BaTiO3. The colloidal form of calcium phosphate nanowires/nanorods/nanospheres (2–5 nm diameter and 30–1000 nm length) and their Au nanoparticle (5–8 nm) composites are prepared, and their piezoelectric properties have been investigated with piezoresponse force microscopy. It has been observed that the anisotropic nanowire structure of calcium phosphate can enhance the piezoelectric property by 2 times and Au nanoparticle conjugation can enhance it up to 10 times with a piezoelectric constant value of 72 pm/V, which is close to the value of the bulk/nanoparticle form of BaTiO3. This enhanced piezoelectric property is shown to enhance the piezocatalytic reactions by 10 times. The approach has been used to design colloidal nano-bioconjugate for selective labeling of cancer cells, followed by wireless cell therapy via medical-grade ultrasound-based intracellular reactive oxygen species generation. The developed approach and material can be extended for wireless therapeutic applications and for controlling intracellular processes.

Although mitochondria have been identified as a potential therapeutic target for the treatment of various diseases, inefficient drug targeting to mitochondria is a major limitation for related therapeutic applications. In the current approach, drug loaded nanoscale carriers are used for mitochondria targeting via endocytic uptake. However, these approaches show poor therapeutic performance due to inefficient drug delivery to mitochondria. Here, we report a designed nanoprobe that can enter the cell via a nonendocytic approach and label mitochondria within 1 h. The designed nanoprobe is <10 nm in size and terminated with arginine/guanidinium that offers direct membrane penetration followed by mitochondria targeting. We found five specific criteria that need to be adjusted in a nanoscale material for mitochondria targeting via the nonendocytic approach. They include <10 nm size, functionalization with arginine/guanidinium, cationic surface charge, colloidal stability, and low cytotoxicity. The proposed design can be adapted for mitochondria delivery of drugs for efficient therapeutic performance.