The specific recognition of cancer cells by the body's immune system is an essential step in initiating antitumor immunity. However, the decreased expression of major histocompatibility complex class I (MHC-1) and overexpression of programmed death ligand 1 (PD-L1) causes insufficient tumor-associated antigens presentation and inactivation of T cells, which accounts for poor immunogenicity. To remodel tumor immunogenicity, herein, a dual-activatable binary CRISPR nanomedicine (DBCN) that can efficiently deliver a CRISPR system into tumor tissues and specifically control its activation is reported. This DBCN is made of a thioketal-cross-linked polyplex core and an acid-detachable polymer shell, which can maintain stability during blood circulation, while detaching a polymer shell to facilitate the cellular internalization of the CRISPR system after entering tumor tissues and ultimately activating gene editing under exogenous laser irradiation, thereby maximizing the therapeutic benefits and reducing potential safety concerns. With the collaborative application of multiple CRISPR systems, DBCN efficiently corrects both dysregulation of MHC-1 and PD-L1 expression in tumors, thus initiating robust T celldependent antitumor immune responses to inhibit malignant tumor growth, metastasis, and recurrence. Given the increasing abundance of CRISPR toolkits, this research provides an appealing therapeutic strategy and a universal delivery platform to develop more advanced CRISPR-based cancer treatments.

The clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR‐related protein 9 (Cas9) genome editing system has attracted much attention due to its powerful genome editing capacity. However, CRISPR‐Cas9 components are easily degraded by acids, enzymes, and other substances in the body fluids after entering the organism, thus efficiently delivering the CRISPR‐Cas9 system into targeted organs or cells has been a central theme for promoting the application of CRISPR‐Cas9 technology. Although several physical methods and viral vectors have been developed for CRISPR‐Cas9 delivery, their clinical application still suffers from disadvantages, such as the risks of mutagenesis, cell damage, and poor specificity. As an alternative, non‐viral nanocarriers hold great promise for circumventing these challenges. Furthermore, with aim to realize more efficient and precise genome editing and reduce the undesirable side effects, stimuli‐responsive nanocarriers are designed for the spatiotemporal CRISPR‐Cas9 delivery in responsive to various stimuli. In this review, we will summarize the recent progress in delivery strategies for CRISPR‐Cas9 genome editing. The mechanisms and advantages of these strategies were reviewed, providing a comprehensive review of the rational design of materials and techniques for efficient and precise genome editing. At last, the potential challenges of current CRISPR‐Cas9 delivery are discussed.