Nanomedicines are attractive paradigms to deliver drugs, contrast agents, immunomodulators, and gene editors for cancer therapy and diagnosis. However, the currently developed nanomedicine suffers from poor serum stability, premature drug release, and lack of responsiveness. Crosslinking strategy can be utilized to overcome these shortcomings by employing stimuli‐responsive chemical bonds to tightly hold the nanostructure and releasing the payloads spatiotemporally in a highly controlled manner. In this Review, we summarize the recently ingenious design of the stimuli‐responsive crosslinked nanomedicines (SCN) in the field of cancer treatment and their advances in circumventing the drawbacks of the conventional drug delivery system. We classify the SCNs into three categories based on the crosslinking strategies, including built‐in, on‐surface, and inter‐particle crosslinking nanomedicines. Thanks to the stimuli‐responsive crosslinkages, SCNs are capable of keeping robust stability during systemic circulation. They also respond to the particular tumoral conditions to experience a series of dynamic changes, such as the changes in size, surface charge, targeting moieties, integrity, and imaging signals. These characteristics allow them to efficiently overcome different biological barriers and substantially improve the drug delivery efficiency, tumor‐targeting ability, and imaging sensitivities. With the examples discussed, we envision that our perspectives can inspire more attempts to engineer intelligent nanomedicine to achieve effective cancer therapy and diagnosis.

Purpose: Immune checkpoint inhibitors (ICIs) in general have shown poor efficacy in bladder cancer (BCa). The purpose of this project was to determine whether photodynamic therapy (PDT) with BCa-specific porphyrin-based PLZ4-nanoparticles (PNP) potentiated ICI. Experimental Design: SV40 T/Ras double-transgenic mice bearing spontaneous BCa and C57BL/6 mice carrying syngeneic bladder cancer models were used to determine the efficacy and conduct molecular correlative studies. Results: PDT with PNP generated reactive oxygen species, induced protein carbonylation and dendritic cell maturation. In SV40 T/Ras double-transgenic mice carrying spontaneous bladder cancer, the median survival was 33.7 days in the control, compared to 44.8 (p=0.0123), 52.6 (p=0.0054) and over 75 (p=0.0001) days in the anti-programmed cell death-1 antibody(anti-PD-1), PNP PDT and combination groups, respectively. At Day 75 when all mice in other groups died, only one in 7 mice in the combination group died. For the direct anti-tumor activity, compared to the control, the ani-PD-1, PNP PDT and combination groups induced a 40.25% (p=0.0003), 80.72% (p<0.0001) and 93.03% (p<0.0001) tumor reduction, respectively. For the abscopal anti-cancer immunity, the anti-PD-1, PNP PDT and combination groups induced tumor reduction of 45.73% (p=0.0001), 54.92% (p<0.0001) and 75.96% (p<0.0001), respectively. The combination treatment also diminished spontaneous and induced lung metastasis. Potential of immunotherapy by PNP PDT is multifactorial. Conclusions: In addition to its potential for photodynamic diagnosis and therapy, PNP PDT can synergize immunotherapy in treating locally advanced and metastatic bladder cancer. Clinical trials are warranted to determine the efficacy and toxicity of this combination.

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This review introduces low-density lipoprotein (LDL) delivery systems, summarizes the research status and progress in targeted diagnosis and therapy, and looks forward to the clinical application of LDL as an effective delivery vehicle.