Clinical applications of many anti-cancer drugs are restricted due to their hydrophobic nature, requiring use of harmful organic solvents for administration, and poor selectivity and pharmacokinetics resulting in off-target toxicity and inefficient therapies. A wide variety of carrier-based nanoparticles have been developed to tackle these issues, but such strategies often fail to encapsulate drug efficiently and require significant amounts of inorganic and/or organic nanocarriers which may cause toxicity problems in the long term. Preparation of nanoformulations for the delivery of water insoluble drugs without using carriers is thus desired, 2 requiring elegantly designed strategies for products with high quality, stability and performance. These strategies include simple self-assembly or involving chemical modifications via coupling drugs together or conjugating them with various functional molecules such as lipids, carbohydrates and photosensitizers. During nanodrugs synthesis, insertion of redox-responsive linkers and tumor targeting ligands endows them with additional characteristics like on-target delivery, and conjugation with immunotherapeutic reagents enhances immune response alongside therapeutic efficacy. This review aims to summarize the methods of making carrier-free nanodrugs from hydrophobic drug molecules, evaluating their performance, and discussing the advantages, challenges, and future development of these strategies.

Nanomedicines have long been expected to significantly enhance cancer treatment. However, their clinical translation is still very limited despite of the world's great efforts during the last 2 decades. One of the reasons is that the transport barriers within tumors restrict their penetration into tumors, with most nanomedicines remaining among the top submicrometer to several micrometers scale. Therefore, there is an extensive interest in the field to understand the tumor microenvironment and develop techniques to boost the penetration of nanomedicines in tumors. This review emphasizes the need of smart nanotechnology to fit the changing requirements of nanomedicines for effective drug delivery, particularly the technologies for deep penetration of nanomedicines in tumor tissues, and explores their mechanisms in order to achieve multistage requirement during the applications of nanomedicines in patients. Finally, the advantages and

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The systemic administration of paclitaxel (PTX)-based combinatorial therapies is significantly restricted due to the multidrug resistance. Curcumin (CUR) not only inhibits cancer-cell proliferation but also reverses the PTX resistance. However, achieving codelivery of these two drugs is a challenge due to their poor water solubility. Herein, we synthesized carrier-free PTX NPs by a facile nanoprecipitation method with the help of CUR and other curcuminoids present in turmeric extract. The prepared NPs demonstrated spherical morphologies with high conformational stability. Experimental studies showed that the presence of both bisdemethoxycurcumin and demethoxycurcumin is essential for the successful formation of spherical and monodisperse NPs. Computational studies revealed that the presence of the more sterically available curcuminoids BMC and DMC makes the self-assembly procedure more adaptable with a higher number of potential conformations that could give rise to more monodisperse PTX-CUR NPs. Compared with PTX alone, PTX-CUR NPs have shown comparable therapeutic efficiency in vitro and demonstrated a higher cellular internalization, highlighting their potential for in vivo applications. The successful formation of PTX-CUR NPs and the understanding of how multiple drugs behave at the molecular level also provide guidance for developing formulations for the synthesis of high-quality and effective carrier-free nanosystems for biomedical applications.