Cancer remains a highly lethal disease in the world. Currently, either conventional cancer therapies or modern immunotherapies are non-tumor-targeted therapeutic approaches that cannot accurately distinguish malignant cells from healthy ones, giving rise to multiple undesired side effects. Recent advances in nanotechnology, accompanied by our growing understanding of cancer biology and nano-bio interactions, have led to the development of a series of nanocarriers, which aim to improve the therapeutic efficacy while reducing off-target toxicity of the encapsulated anticancer agents through tumor tissue-, cell-, or organelle-specific targeting. However, the vast majority of nanocarriers do not possess hierarchical targeting capability, and their therapeutic indices are often compromised by either poor tumor accumulation, inefficient cellular internalization, or inaccurate subcellular localization. This Review outlines current and prospective strategies in the design of tumor tissue-, cell-, and organelle-targeted cancer nanomedicines, and highlights the latest progress in hierarchical targeting technologies that can dynamically integrate these three different stages of static tumor targeting to maximize therapeutic outcomes. Finally, we briefly discuss the current challenges and future opportunities for the clinical translation of cancer nanomedicines.

Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.

Chemotherapy turns tumor cells into “tumor vaccines” by immunogenic cell death (ICD). However, it remains a challenge to exploit chemotherapy‐induced “tumor vaccines” for solid cancer immunotherapy due to the inefficient effector T cells activation and tumor microenvironment immunosuppression. Here, a matrix metalloprotease 2 responsive liposome (PEG‐FA‐Lip) composed of cleavable PEG chains covering the folate (FA)‐modified liposome is developed to deliver ICD inducer doxorubicin. In breast cancer‐bearing mice, PEG‐FA‐Lip targets both 4T1 breast cancer cells and M2‐tumor associated macrophages (M2‐TAMs) via FA‐receptor mediated endocytosis, resulting in abundant “tumor vaccines” and efficient elimination of M2‐TAMs. The combination of local cytosine‐phosphate‐guanine (CpG) therapy facilitates PEG‐FA‐Lip induced “tumor vaccines” to effectively arouse systematic effector T cells immune response through promoting dendritic cell maturation and immunostimulatory cytokines secretion. The simultaneous elimination of M2‐TAMs ensures the activated effector T cells exert antitumor immunity within tumor via decreasing immunosuppressive cytokines secretion and tumor infiltration of Treg cells. After receiving the combined treatment, 30.1% of breast cancer‐bearing mice (initial tumor volume > 100 mm³) achieves the goal of tumor eradication. Remarkably, this combination therapy greatly inhibits lung metastasis and controls the growth of already metastasized breast cancers (initial tumor volume > 100 mm³).