Macrophages hold great potential in cancer drug delivery because they can sense chemotactic cues and home to tumors with high efficiency. However, it remains a challenge to load large amounts of therapeutics into macrophages without compromising cell functions. Here we report a silica-based drug nanocapsule approach to solve this issue. Our nanocapsule consists of a drug-silica complex filling and a solid silica sheath, and it is designed to minimally release drug molecules in the early hours of cell entry. While taken up by macrophages at high rates, the nanocapsules minimally affect cell migration in the first 6–12 h, buying time for macrophages to home to tumors and release drugs in situ. In particular, we show that doxorubicin (Dox) as a representative drug can be loaded into macrophages up to 16.6 pg/cell using this approach. When tested in a U87MG xenograft model, intravenously (i.v.) injected Dox-laden macrophages show comparable tumor accumulation as untreated macrophages. Therapy leads to efficient tumor growth suppression, while causing little systematic toxicity. Our study suggests a new cell platform for selective drug delivery, which can be readily extended to the treatment of other types of diseases.

Highlights d The DNA repair nuclease MRE11A is located in mitochondria d Mitochondrial MRE11A protects mtDNA from oxidation and cytoplasmic leakage d MRE11A low T cells fail to produce ATP and undergo caspase-1-dependent pyroptosis d MRE11A loss of function results in tissue inflammation

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Mitochondrial dysfunctions are recognized as major factors for various diseases including cancer, cardiovascular diseases, diabetes, neurological disorders, and a group of diseases so called “mitochondrial dysfunction related diseases”. One of the major hurdles to gain therapeutic efficiency in diseases where the targets are located in the mitochondria is the accessibility of the targets in this compartmentalized organelle that imposes barriers towards internalization of ions and molecules. Over the time, different tools and techniques were developed to improve therapeutic index for mitochondria acting drugs. Nanotechnology has unfolded as one of the logical and encouraging tools for delivery of therapeutics in controlled and targeted manner simultaneously reducing side effects from drug overdose. Tailor-made nanomedicine based therapeutics can be an excellent tool in the toolbox for diseases associated with mitochondrial dysfunctions. In this review, we present an extensive coverage of possible therapeutic targets in different compartments of mitochondria for cancer, cardiovascular, and mitochondrial dysfunction related diseases.

Anticancer platinum (Pt) complexes have long been pronounced as one of the biggest success stories in the history of medicinal inorganic chemistry. Yet there still remains the hunt for the “magic bullet” which can satiate the requisites of an effective chemotherapeutic drug formulation. Pt(IV) complexes are kinetically more inert that the Pt(II) congeners and offer the opportunity to append additional functional groups/ligands for prodrug activation, tumor targeting or drug delivery. The ultimate aim for functionalization is to enhance the tumor selective action and attenuate systemic toxicity of the drugs. Moreover, increase in cellular accumulation to surmount the resistance of the tumor against the drugs is also of paramount importance in drug development and discovery. In this review, we will address some of the attempts in our lab to develop Pt(IV) prodrugs that can be activated and their targeted delivery using robust nanotechnology platforms.