Cardiovascular disease, including heart failure, is one of the leading causes of mortality in the world. Delivery of nano-objects as carriers for markers, drugs or therapeutic genes to cellular organelles has the potential to sharply increase the efficiency of diagnostic and treatment protocols for heart failure. However, cardiac cells present special problems to the delivery of nano-objects, and the number of papers devoted to this important area is remarkably small. The present review discusses fundamental aspects, problems and perspectives in the delivery of nano-objects to functional sub-domains of failing cardiomyocytes. What size nano-objects can reach cellular sub-domains in failing hearts? What are the mechanisms for their permeation through the sarcolemma? How can we improve the delivery of nano-objects to the sub-domains? Answering these questions is fundamental to identifying cellular targets within the failing heart and the development of nanocarriers for heart-failure therapy at the cellular level.