Nanoparticles have been widely used in tumor targeted drug delivery, while the antitumor effects are not always satisfactory due to the limited penetration and retention. As we all know, there is a paradox that nanoparticles with large sizes tend to distribute around tumor blood vessels rather than penetrate into tumor parenchyma, while smaller sizes can penetrate deeply but with poor tumor retention. In recent days, an intelligent, size-tunable strategy provided a solution to determine the size problem of nanoparticles and exhibited good application prospects. In this review, we summarize series of stimuli-induced aggregation and shrinkage strategies for tumor targeted drug delivery, which can significantly increase the retention and penetration of nanodrugs in tumor sites at the same time, thus promoting treatment efficacy. Internal (enzymes, pH, and redox) and external (light and temperature) stimuli are introduced to change the morphology of the original nanodrugs through protonation, hydrophobization, hydrogen bond, π–π stacking and enzymolysis-resulted click reactions or dissociation, etc. Apart from applications in oncotherapy, size-tunable strategies also have a great prospect in the diagnosis and real time bioimaging fields, which are also introduced in this review. Finally, the potential challenges for application and future directions are thoroughly discussed, providing guidance for further clinical transformation.

Due to the ability of the blood-brain barrier (BBB) to prevent the entry of drugs into the brain, it is a challenge to treat central nervous system disorders pharmacologically. The development of nanotechnology provides potential to overcome this problem. In this review, the barriers to brain-targeted drug delivery are reviewed, including the BBB, blood-brain tumor barrier (BBTB), and nose-to-brain barrier. Delivery strategies are focused on overcoming the BBB, directly targeting diseased cells in the brain, and dual-targeted delivery. The major concerns and perspectives on constructing brain-targeted delivery systems are discussed.

The past decades have witnessed great progress in cancer immunotherapy, which has profoundly revolutionized oncology, whereas low patient response rates and potential immune‐related adverse events remain major clinical challenges. With the advantages of controlled delivery and modular flexibility, cancer nanomedicine has offered opportunities to strengthen antitumor immune responses and to sensitize tumor to immunotherapy. Furthermore, tumor‐microenvironment (TME)‐responsive nanomedicine has been demonstrated to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner, increasing patient response rates to immunotherapy and reducing the immune‐related side effects simultaneously. Here, the recent progress of TME‐responsive nanomedicine for cancer immunotherapy is summarized, which responds to the signals in the TME, such as weak acidity, reductive environment, high‐level reactive oxygen species, hypoxia, overexpressed enzymes, and high‐level adenosine triphosphate. Moreover, the potential to combine nanomedicine‐based therapy and immunotherapeutic strategies to overcome each step of the cancer‐immunity cycle and to enhance antitumor effects is discussed. Finally, existing challenges and further perspectives in this rising field with the hope for improved development of clinical applications are discussed.

Hyaluronic acid (HA) is a natural polysaccharide that has gained much attention due to its biocompatibility, enzyme degradation capacity and active tumor targeting capacity. Its receptor, CD44, is overexpressed in many kinds of cancers and is associated with tumor progress, infiltration and metastasis. Therefore, many researchers have developed various HA-based drug delivery systems for CD44-mediated tumor targeting. In this review, we systemically overview the basic theory of HA, its receptor and hyaluronidase, then we categorize the studies in HA-based drug delivery systems according to the functions of HA, including tumor-targeting materials, enzyme-sensitive biodegradable modality, pH-sensitive component, reduction-sensitive component, and the gel backbone. Finally, the perspective is discussed.