dense extracellular matrix, prevent the cell-targeting therapeutic agents from penetrating deep into tumors and compromising their therapeutic effects. [1] As a fascinating non-cell-targeting strategy, the penetration-independent tumor blockade therapy obstructs the communications between the tumor and surrounding normal tissues by blocking tumor vasculature or building physical barriers. [2] Recently, vessel-targeted blockade therapy, including vascular disruption, arterial embolization, thrombosis induction, and so forth, [3] results in tumor malnutrition and accumulation of detrimental metabolites, ultimately leading to the ischemia and necrosis of central tumor region. [4] However, the viable marginal tumor tissue, cardiac ischemia, abnormal blood pressure, reversible neurologic complications, or other possible side effects have limited its clinical translation. [5] The construction of an artificial extracellular matrix (AECM) in the peripheral tumor tissue is another strategy for tumor blockade therapy. [6] AECM functions as an exogenous barrier and restrains the proliferation, migration, and invasion of cancer cells. For instance, Xu's group first reported fibrous nanonet formed by a small D-peptide derivative in the pericellular space. [7] The nanonets entrapped the secretory proteins and blocked cell Tumor blockade therapy is a promising penetration-independent antitumor modality, which effectively inhibits the exchange of nutrients, oxygen, and information between the tumor and surrounding microenvironments. However, the current blockade therapy strategies have limited antitumor efficacy due to defects of inadequate tumor obstruction, possible side effects, and short duration. For these reasons, a facilely synthesized versatile polymer 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)alendronate (DSPE-PEG-ALN, DPA) is developed to initiate the formation of biomineral shell around osteosarcoma as a potent physical barrier. The DSPE moiety shares a similar chemical structure with the cytomembrane, allowing the membrane insertion of DPA. The bisphosphonic acid groups in ALN attract ions to realize biomineralization around cells. After injection in the invasive osteosarcoma tissue, DPA inserts into the cytomembrane, induces continuous mineral deposition, and ultimately builds a physical barrier around the tumor. Meanwhile, ALN in DPA alleviates bone destruction by suppressing the activity of osteoclasts. Through hindering the exchange of necessary substances, the biomineralization coating inhibits the growth of primary osteosarcoma and pulmonary metastasis simultaneously. Therefore, the multifunctional polymer-initiating blockade therapy provides a promising modality for tumor inhibition in clinics with high efficacy and negligible side effects.
