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Malignant tumor, the leading cause of death worldwide, poses a serious threat to human health. For decades, natural product has been proven to be an essential source for novel anticancer drug discovery. Shikonin (SHK), a natural molecule separated from the root of Lithospermum erythrorhizon, shows great potential in anticancer therapy. However, its further clinical application is significantly restricted by poor bioavailability, adverse effects, and non-selective toxicity. With the development of nanotechnology, nano drug delivery systems have emerged as promising strategies to improve bioavailability and enhance the therapeutic efficacy of drugs. To overcome the shortcoming of SHK, various nano drug delivery systems such as liposomes, polymeric micelles, nanoparticles, nanogels, and nanoemulsions, were developed to achieve efficient delivery for enhanced antitumor effects. Herein, this review summarizes the anticancer pharmacological activities and pharmacokinetics of SHK. Additionally, the latest progress of SHK nanomedicines in cancer therapy is outlined, focusing on long circulation, tumor targeting ability, tumor microenvironment responsive drug release, and nanosystem-mediated combination therapy. Finally, the challenges and prospects of SHK nanomedicines in the future clinical application are spotlighted.

According to the World Health Organization, there were approximately 9.96 million deaths from cancer in 2020. Although researchers are actively searching for new treatments, the outcomes have been unsatisfactory, with limited improvement in the five-year survival rates. [2] Until now, immunotherapy has become one of the four pillars of clinical cancer treatment, along with surgery, chemotherapy, and radiotherapy. [3] It endows the body with the ability to eliminate tumors and prevent recurrence by stimulating the immune system, thus extending the survival time of patients. [4] Checkpoint inhibitors, pericyte therapy, lymphocyte-promoting cytokines, agonistic antibodies against co-stimulatory receptors, and cancer vaccines have been developed in recent years. [5] Due to the limited targeting and inherent toxicity of immune medicines, systemic use may result in autoimmune illness or non-specific inflammation. [6,7] In addition, tumor heterogeneity, clonal diversity, complex genetic mutations, and complex microenvironment all contribute to the poor outcomes of current tumor treatments. [8,9] Fortunately, previous studies have demonstrated that chemotherapy, photodynamic therapy (PDT), and photothermal therapy (PTT) can induce immunogenic cell death (ICD), which can enhance the immunotherapy effect. [10,11] However, the precise delivery of the co-therapeutic agents to the tumor site becomes the main challenge. [12] The rapid development of nanotechnology has promoted the application of nanomedicines in tumor therapy. [13] Nanomedicines can accumulate at tumor sites via the enhanced permeability and retention (EPR) effect and deliver drugs to specific tumor cells, thereby reducing off-target toxicity. [14,15] Notably, stimulus-responsive nanomedicines as a promising drug delivery method have received more and more attention. [16,17] The smart nano-platforms can achieve rapid drug release in response to external stimulus (ultrasound, mechanical stimuli, magnetic fields, lasers, etc.) or internal stimulus in the tumor microenvironment (TME) (weak acidity, high glutathione (GSH) levels, reactive oxygen species (ROS), enzymes, adenosine triphosphate (ATP), etc.), thus improving tumor treatment outcomes. [18] Polysaccharides, a family of potential biomaterials, possess unique advantages such as unique physicochemical properties, Cancer immunotherapy is a promising antitumor approach, whereas nontherapeutic side effects, tumor microenvironment (TME) intricacy, and low tumor immunogenicity limit its therapeutic efficacy. In recent years, combination immunotherapy with other therapies has been proven to considerably increase antitumor efficacy. However, achieving codelivery of the drugs to the tumor site remains a major challenge. Stimulus-responsive nanodelivery systems show controlled drug delivery and precise drug release. Polysaccharides, a family of potential biomaterials, are widely used in the development of stimulus-responsive nanomedicines due to their unique physicochemical properties, biocompatibility, and modifiab...

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