Efficient cellular delivery of biologically active molecules is one of the key factors that affect the discovery and development of novel drugs. The plasma membrane is the first barrier that prevents direct translocation of chemic entities, and thus obstructs their efficient intracellular delivery. Generally, hydrophilic small molecule drugs are poor permeability that reduce bioavailability and thus limit the clinic application. The cellular uptake of macromolecules and drug carriers is very inefficient without external assistance. Therefore, it is desirable to develop potent delivery systems for achieving effective intracellular delivery of chemic entities. Apart from of the types of delivery strategies, the composition of the cell membrane is critical for delivery efficiency due to the fact that cellular uptake is affected by the interaction between the chemical entity and the plasma membrane. In this review, we aimed to develop a profound understanding of the interactions between delivery systems and components of the plasma membrane. For the purpose, we attempt to present a broad overview of what delivery systems can be used to enhance the intracellular delivery of poorly permeable chemic entities, and how various delivery strategies are applied according to the components of plasma membrane.

Protein/antibody therapeutics have exhibited the advantages of high specificity and activity even at an extremely low concentration compared to small molecule drugs. However, they are accompanied by unfavorable physicochemical properties such as fragile tertiary structure, large molecular size, and poor penetration of the membrane, and thus the clinical use of protein drugs is hindered by inefficient delivery of proteins into the host cells. To overcome the challenges associated with protein therapeutics and enhance their biopharmaceutical applications, various protein‐loaded nanocarriers with desired functions, such as lipid nanocapsules, polymeric nanoparticles, inorganic nanoparticles, and peptides, are developed. In this review, the different strategies for intracellular delivery of proteins are comprehensively summarized. Their designed routes, mechanisms of action, and potential therapeutics in live cells or in vivo are discussed in detail. Furthermore, the perspective on the new generation of delivery systems toward the emerging area of protein‐based therapeutics is presented as well.

Mitochondria are the powerhouse of cells. They are vital organelles that maintain cellular function and metabolism. Dysfunction of mitochondria results in various diseases with a great diversity of clinical appearances. In the past, strategies have been developed for fabricating subcellular‐targeting drug‐delivery nanocarriers, enabling cellular internalization and subsequent organelle localization. Of late, innovative strategies have emerged for the smart design of multifunctional nanocarriers. Hierarchical targeting enables nanocarriers to evade and overcome various barriers encountered upon in vivo administration to reach the organelle with good bioavailability. Stimuli‐responsive nanocarriers allow controlled release of therapeutics to occur at the desired target site. Synergistic therapy can be achieved using a combination of approaches such as chemotherapy, gene and phototherapy. In this Review, we survey the field for recent developments and strategies used in the smart design of nanocarriers for mitochondria‐targeted therapeutics. Existing challenges and unexplored therapeutic opportunities are also highlighted and discussed to inspire the next generation of mitochondrial‐targeting nanotherapeutics.

MicroRNAs are small regulatory noncoding RNAs that regulate various biological processes. Herein, we will present the development of the strategies for intracellular miRNAs delivery, and specially focus on the rational designed routes, their mechanisms of action, as well as potential therapeutics used in the host cells or in vivo studies.